Clinical impact of allergy and pre-medication in CT studies with low-osmolality intravenous iodinated contrast media.

AIM: To evaluate the occurrence and severity of allergic reactions to iodinated contrast media (ICM), including associated risk factors and the impact of pre-medication. MATERIALS AND METHODS: Data on patients who had experienced allergic reactions during outpatient computed tomography (CT) examinations between January 2014 and September 2018 were analysed retrospectively. Response severity was assessed according to validated criteria. A control group was selected among individuals who underwent CT during the study period and did not experience allergic reactions. RESULTS: Screening of 36,920 CT studies revealed 74 (0.2%) individuals with systemic reactions to ICM. No significant differences in patient characteristics were found among patients who experienced mild (n=54), moderate (n=17), or severe (n=4) reactions. Previous ICM allergy was reported in 10 patients (13.3%). Patients with a history of ICM allergy had mild (9/10) or moderate (1/10) reactions, with one individual showing decreased intensity of the allergic response compared to a previous event. Within the control group, four patients (4%) had previous ICM allergy. In these individuals, lack of allergic reactions could not be attributed to pre-medication. All patients with severe reactions did not have a prior history of ICM allergy. CONCLUSION: Severe allergic reactions to ICM are rare, lack significant risk factors, and do not appear to be impacted by pre-medication. The findings presented herein highlight the need for prospective work that will re-evaluate the yield of pre-medication protocols.

Cardiac arrhythmias amongst hospitalised Coronavirus 2019 (COVID-19) patients: Prevalence, characterisation, and clinical algorithm to classify arrhythmic risk.

OBJECTIVES: A significant proportion of COVID-19 patients may have cardiac involvement including arrhythmias. Although arrhythmia characterisation and possible predictors were previously reported, there are conflicting data regarding the exact prevalence of arrhythmias. Clinically applicable algorithms to classify COVID patients' arrhythmic risk are still lacking, and are the aim of our study. METHODS: We describe a single-centre cohort of hospitalised patients with a positive nasopharyngeal swab for COVID-19 during the initial Israeli outbreak between 1/2/2020 and 30/5/2020. The study's outcome was any documented arrhythmia during hospitalisation, based on daily physical examination, routine ECG's, periodic 24-hour Holter, and continuous monitoring. Multivariate analysis was used to find predictors for new arrhythmias and create classification trees for discriminating patients with high and low arrhythmic risk. RESULTS: Out of 390 COVID-19 patients included, 28 (7.2%) had documented arrhythmias during hospitalisation, including 23 atrial tachyarrhythmias, combined atrial fibrillation (AF), and ventricular fibrillation, ventricular tachycardia storm, and 3 bradyarrhythmias. Only 7/28 patients had previous arrhythmias. Our study showed a significant correlation between disease severity and arrhythmia prevalence (P < .001) with a low arrhythmic prevalence amongst mild disease patients (2%). Multivariate analysis revealed background heart failure (CHF) and disease severity are independently associated with overall arrhythmia while age, CHF, disease severity, and arrhythmic symptoms are associated with tachyarrhythmias. A novel decision tree using age, disease severity, CHF, and troponin levels was created to stratify patients into high and low risk for developing arrhythmia. CONCLUSIONS: Dominant arrhythmia amongst COVID-19 patients is AF. Arrhythmia prevalence is associated with age, disease severity, CHF, and troponin levels. A novel simple Classification tree, based on these parameters, can discriminate between high and low arrhythmic risk patients.

Exogenous interleukin-2 can rescue in-vitro T cell activation and proliferation in patients with a novel capping protein regulator and myosin 1 linker 2 mutation.

Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28-mediated co-signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)-2 on in-vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5-10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25-base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in-vitro with the addition of IL-2 in different concentrations. CD25 and interferon (IFN)-γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8+ and CD4+ T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8+ T cells from all patients demonstrated significantly reduced IFN-γ production. When cells derived from CARMIL2-deficient patients were treated with IL-2, CD25 and IFN-γ production increased in a dose-dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL-2. In conclusion, we found that IL-2 rescued T cell activation and proliferation in CARMIL2-deficient patients. Thus, IL-2 should be further studied as a potential therapeutic modality for these patients.

Alopecia areata in patients with systemic lupus erythematosus treated with belimumab: a plausible association.

Belimumab, an anti-B-lymphocyte stimulator monoclonal antibody, was recently approved for the treatment of systemic lupus erythematosus. Alopecia areata is characterized by an acute immune-mediated hair loss. Herein, we report on three adult systemic lupus erythematosus patients who developed alopecia areata in association with belimumab treatment. Alopecia areata was resolved in all three patients and belimumab was discontinued in two of them. Thus, in the current report, we explore the plausible link between alopecia areata and belimumab.

Hydroxychloroquine desensitization, an effective method to overcome hypersensitivity-a multicenter experience.

Hydroxychloroquine (HCQ) is widely used to treat autoimmune/rheumatic diseases such as systemic lupus erythematosus (SLE). The immune modulation effects of HCQ have been highlighted as beneficial for maintaining remission of SLE as well as ameliorating skin, joint and other manifestations. Moreover, HCQ exposure for prolonged periods as well as during pregnancy is considered safe, therefore it is recommended for the vast majority of SLE patients. Although HCQ therapy requires follow-up by a specialist, its most common side effects are mild gastrointestinal disturbances, sensitivity to light and skin rashes. Of these side effects, hypersensitivity skin reactions have been suggested to play a role in reduced compliance to HCQ therapy. In the current study we present a two-stage HCQ desensitization protocol that was successfully implemented among 12 out of 13 patients. We exhibit that prolonged HCQ oral desensitization is an effective method for overcoming mild to moderate late hypersensitivity reactions and thoroughly address possible mechanisms of action.

Transgenic over-expression of mammalian heparanase delays prion disease onset and progression.

Cellular heparan sulfate (HS) has a dual role in scrapie pathogenesis; it is required for PrP(Sc) (scrapie prion protein) formation and facilitates infection of cells, mediating cellular uptake of prions. We examined the involvement of heparanase, a mammalian endoglycosidase degrading HS, in scrapie infection. In cultured cells, heparanase treatment or over-expression resulted in a profound decrease in PrP(Sc). Moreover, disease onset and progression were dramatically delayed in scrapie infected transgenic mice over-expressing heparanase. Together, our results provide direct in vivo evidence for the involvement of intact HS in the pathogenesis of prion disease and the protective role of heparanase both in terms of susceptibility to infection and disease progression.

Retained placental tissue as an emerging cause for malpractice claims.

BACKGROUND: Removal of retained placental tissue postpartum and retained products of conception (RPOC) abortion is done by uterine curettage or hysteroscopy. Trauma to the endometrium from surgical procedures, primarily curettage, can cause intrauterine adhesions (Asherman's syndrome) and subsequent infertility. The incidence of malpractice claims relating to intrauterine adhesions is rising, justifying reevaluation of the optimal way of handling these complications. OBJECTIVES: To review malpractice claims regarding intrauterine adhesions, and to explore the clinical approach that might reduce those claims or improve their medical and legal outcomes. METHODS: We examined 42 Asherman's syndrome claims handled by MCI, the largest professional liability insurer in Israel. The clinical chart of each case was reviewed and analyzed by the event preceding the adhesion formations, timing and mode of diagnosis, and outcome. We also assessed whether the adverse outcome was caused by substandard care and it it could have been avoided by different clinical practice. The legal outcome was also evaluated. RESULTS: Forty-seven percent of the cases occurred following vaginal delivery, 19% followed cesarean section, 28% were RPOC following a first-trimester pregnancy termination, and 2% followed a second-trimester pregnancy termination. CONCLUSIONS: It is apparent that due to the lack of an accepted management protocol for cases of RPOC, it is difficult to legally defend those cases when the complication of Asherman syndrome develops.

Newborn oxygen saturation at mild altitude versus sea level: implications for neonatal screening for critical congenital heart disease.

AIM: To determine the normal SpO2 in healthy term newborns at mild altitude (MA, 780 metres) compared with sea level (SL), within the context of universal screening for critical congenital heart disease (CCHD). METHODS: We studied 199 (119 at MA and 80 at SL) consecutively born healthy newborns. SpO2 recordings were at 24-72 h using Masimo SET Radical-7 on the right hand and left foot. RESULTS: Mean SpO2 was lower at MA compared with SL in the right hand (97.86 ± 1.58 vs 98.28 ± 1.41, p = 0.05) and left foot (98.49 ± 1.35 vs 98.90 ± 1.16, p = 0.03). No infant with SpO2 <95% had CCHD. Extrapolating with predicted regression lines set at 95% CI, a SpO2 cut-off of 95% would result in up to 3.5 times more false-positive screens at MA compared with SL. CONCLUSIONS: At MA, SpO2 is approximately 0.4% lower compared with SL. Our study supports the AAP recommendation suggesting algorithm cut-offs may need adjustment in high-altitude nurseries and suggest broadening it to MA as well.

Coenzyme Q10 in the Treatment of Heart Failure with Preserved Ejection Fraction: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common in elderly people and is increasing in prevalence. No specific treatment for this condition exists. Coenzyme Q10 (CoQ10) is an essential cofactor for energy production, with reduced levels being noted in HF. Previous studies have suggested a possible role for CoQ10 in the treatment of HF. This study examined the effect of CoQ10 supplementation on diastolic function in HFpEF patients. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial including patients aged > 55 years presenting with New York Heart Association class II-IV heart failure symptoms and left ventricular ejection fraction > 50%, with impaired diastolic function. Echocardiography and levels of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed at baseline and following 4 months of CoQ10 or placebo supplementation. RESULTS: A total of 39 patients were enrolled-19 in the CoQ10 group and 20 in the placebo group. Baseline clinical characteristics were similar between groups, while compliance was high and also similar between the CoQ10 and placebo groups. There was no significant effect of treatment on indices of diastolic function (difference in the lateral E/e' ratio: -0.86 ± 6.57 in the CoQ10 group, +0.18 ± 3.76 in the placebo group; p = 0.561) or on serum NT-proBNP levels (- 72 pg/mL vs. - 42 pg/mL; p = 0.195). CONCLUSIONS: In this pilot trial in elderly patients with HFpEF, treatment with CoQ10 did not significantly affect echocardiographic indices of diastolic function and serum NT-proBNP levels. TRIAL REGISTRATION: This trial was registered in the US National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov identifier: NCT02779634).

γδT Cells Are Essential for Orthodontic Tooth Movement.

Sustained mechanical forces applied to tissue are known to shape local immunity. In the oral mucosa, mechanical stress, either naturally induced by masticatory forces or externally via mechanical loading during orthodontic tooth movement (OTM), is translated, in part, by T cells to alveolar bone resorption. Nevertheless, despite being considered critical for OTM, depletion of CD4+ and CD8+ T cells is reported to have no impact on tooth movement, thus questioning the function of αßT cells in OTM-associated bone resorption. To further address the role of T cells in OTM, we first characterized the leukocytes residing in the periodontal ligament (PDL), the tissue of interest during OTM, and compared it to the neighboring gingiva. Unlike the gingiva, monocytes and neutrophils represent the major leukocytes of the PDL. These myeloid cells were also the main leukocytes in the PDL of germ-free mice, although at lower levels than SPF mice. T lymphocytes were more enriched in the gingiva than the PDL, yet in both tissues, the relative fraction of the γδT cells was higher than the αß T cells. We thus sought to examine the role of γδT cells in OTM. γδT cells residing in the PDL were mainly Vγ6+ and produced interleukin (IL)-17A but not interferon-γ. Using Tcrd-GDL mice allowing conditional ablation of γδT cells in vivo, we demonstrate that OTM was greatly diminished in the absence of γδT cells. Further analysis revealed that ablation of γδT cells decreased early IL-17A expression, monocyte and neutrophil recruitment, and the expression of the osteoclastogenic molecule receptor activator of nuclear factor-κß ligand. This, eventually, resulted in reduced numbers of osteoclasts in the pressure site during OTM. Collectively, our data suggest that γδT cells are essential in OTM for translating orthodontic mechanical forces to bone resorption, required for relocating the tooth in the alveolar bone.

Association of Contemporary Statin Pretreatment Intensity and LDL-C Levels on the Incidence of STEMI Presentation.

Constituting hypolipidemic and pleiotropic effects, statins stabilize coronary artery plaque and may prevent STEMI events. This study investigated the association between contemporary statin pretreatment intensity, low-density lipoprotein cholesterol (LDL-C) levels, and the type of acute coronary syndrome (ACS) presentation: STEMI vs. NSTE-ACS. Data were drawn from the ACS Israeli Survey (ACSIS), a biennial prospective national survey that took place in 2008-2018. The rate of STEMI vs. NSTE-ACS was calculated by statin use, including statin intensity (high-intensity statin therapy (HIST) and low-intensity statin therapy (LIST) prior to the index ACS event. Among 5103 patients, 2839 (56%) were statin-naive, 1389 (27%) used LIST and 875 (17%) used HIST. Statin pretreated patients were older and had a higher rates of co-morbidities, cardiovascular disease history and pretreatment with evidence-based medications. STEMI vs. NSTE-ACS was lower among HIST vs. LIST vs. statin-naive patients (31.0%, 37.8%, and 54.0%, respectively, p for trend < 0.001). Multivariate analysis revealed that HIST was independently associated with lower STEMI presentation (ORadj 0.70; 95% CI 0.57-0.86), while LIST (ORadj 0.92; 95% CI 0.77-1.10) and LDL-C < 70 mg/dL (ORadj 0.96; 95% CI 0.82-1.14) were not. In conclusion, among patients admitted with ACS, pretreatment with HIST was independently associated with a lower probability of STEMI presentation, while LIST and LDL-C < 70 mg/dL were not.

Peanuts: gibberellin antagonists and genetically controlled differences in growth habit.

Treatment of peanuts with gibberellin changed the orientation of lateral branches of runners to that of erect ones, and two growth retardants changed those of the erect type to a more horizontal orientation. Little or no difference was found in amounts of endogenous gibberellin in the two types of plants, but amount of native gibberellic acid antagonists was higher in runner plants. Furthermore, runner plants contained a particular gibberellic acid inhibitor not found in erect plants. Applications of various auxins, antiauxins, and a cytokinin had no effect on tropistic growth of the side branches.

Goal orientations in negotiations: the influence of goal orientations on fixed-pie perceptions and bargaining outcomes.

As is the case for other achievement situations, people may approach negotiations emphasizing outcome and/or process goals. This paper examines the effects of process goal orientation (PGO) and outcome goal orientation (OGO) on individuals' fixed-pie perceptions and the negotiation of joint outcomes. Process and outcome goal orientations are associated with different personal beliefs about the world. We hypothesized that persons who are primarily oriented toward outcome goals, based on their fixed-entity perception of the world, would mainly concentrate on the final results or on the outcomes of the negotiation. They would tend to perceive negotiations as fixed, zero-sum, competitive situations, which have to be "won" by one of the parties at the expense of the other. On the other hand, we predicted that people who are strongly process-oriented, based on their malleable-entity perception of the world, would focus mainly on formulating and mastering the best strategies that lead to successful resolution of the negotiation. They would perceive positions to be "malleable" and, hence, would tend to perceive the negotiation as a non zero-sum situation. Additionally, the interaction between the two types of goal orientations and its effect on the parties' joint negotiation outcomes was examined. Results of two empirical studies indicated that OGO was significantly positively associated with fixed-pie bias (Study 1). The significant interaction between PGO and OGO (Study 2) demonstrated that a strong OGO combined with a strong PGO led to the best joint negotiation outcomes. Implications for goal orientation and negotiation theories are discussed.

Sex-linked difference in blood oxygen saturation.

BACKGROUND: It is not known whether SpO2 in healthy volunteers is affected by sex. OBJECTIVE: To evaluate whether there are differences in SpO2 between young healthy adult males and females and to evaluate whether the differences are already present at birth. METHODS: We studied two cohorts of patients. The first one consisted of young adult volunteers (105 males and 102 females). In these patients, SpO2 was measured as well as selected anthropometric variables (height, weight), vital signs (respiratory rate, pulse rate and body temperature) and obtained data on menstrual cycle phase of the female participants. For the second cohort, we reanalyzed data from a previous prospective study that was performed to compare SpO2 of newborns infants born at different altitudes (sea level or 760 m above sea level). MEASUREMENTS AND MAIN RESULTS: In young male adults, mean SpO2 was 97.1% ± 1.2% versus 98.6% ± 1.0% in females (P < .001). This difference remained significant (P = .002) after correction for BMI, BSA and age, variables that were significantly different between sexes in univariate analysis. The SpO2 in females was unaffected by menstrual phase. In contrast to findings in adults, there were no significant differences in SpO2 measurements in newborn infants attributable to sex. CONCLUSIONS: Healthy young female adults have a higher (1.5%) SpO2 than their male counterparts. This difference is not yet present at birth. Further studies are needed to determine the timing of sex-differences, and to better define the mechanism(s) behind this observation.

Nuclear relocalization of the pre-mRNA splicing factor PSF during apoptosis involves hyperphosphorylation, masking of antigenic epitopes, and changes in protein interactions.

The spatial nuclear organization of regulatory proteins often reflects their functional state. PSF, a factor essential for pre-mRNA splicing, is visualized by the B92 mAb as discrete nuclear foci, which disappeared during apoptosis. Because this mode of cell death entails protein degradation, it was considered that PSF, which like other splicing factors is sensitive to proteolysis, might be degraded. Nonetheless, during the apoptotic process, PSF remained intact and was N-terminally hyperphosphorylated on serine and threonine residues. Retarded gel migration profiles suggested differential phosphorylation of the molecule in mitosis vs. apoptosis and under-phosphorylation during blockage of cells at G1/S. Experiments with the use of recombinant GFP-tagged PSF provided evidence that in the course of apoptosis the antigenic epitopes of PSF are masked and that PSF reorganizes into globular nuclear structures. In apoptotic cells, PSF dissociated from PTB and bound new partners, including the U1--70K and SR proteins and therefore may acquire new functions.

Enhanced proteolysis of pre-mRNA splicing factors in myeloid cells.

OBJECTIVE: Molecular identification and characterization of the bone marrow nuclear protein detected by the B92 monoclonal antibody. MATERIALS AND METHODS: The protein was purified to homogeneity from acute myeloid leukemia cells and was subjected to peptide digestion and amino acid sequencing. Identified sequences were used to screen a bone marrow cDNA library in search of matching transcripts. The protein was further studied in different cells and tissues by examination of protease inhibitors and harsh lytic conditions and during apoptosis in HL-60 cells. RESULTS: We found that the apparent bone marrow specific protein is a 47 kD proteolytic cleavage product of PSF, an essential pre-mRNA splicing factor. PSF is completely cleaved to p47 during lysis of immature myeloid cells due to potent proteolytic activity found in these cells but is rare in other cells and tissues. Furthermore, p47 is abundant in intact normal and tumor myeloid cells while in other cell types it is undetectable. The cleavage of PSF is accompanied by digestion of the PTB splicing regulator but not other proteins tested. In contrast, during apoptosis PTB is degraded while PSF remains intact. CONCLUSIONS: The bone marrow 47 kD protein is a fragment constituting the N-terminal, protease-resistant half of the splicing factor PSF. Proteolytic degradation of PSF specifically occurs in intact myeloid cells and this process is enhanced upon myeloid cell lysis.

Adhesion molecules involved in the interactions between early T cells and mesenchymal bone marrow stromal cells.

We previously reported that among the various thymic lymphocyte subpopulations, the immature T cells preferentially adhere to mesenchymal bone marrow stroma. In the present study we examined the interactions between phenotypically defined populations of early T cells and stromal cell lines. The immature T cells segregated into two subpopulations according to their adhesive capacity. Whereas the majority of the adherent CD4-CD8- T cells were devoid of CD3/TCRalphabeta, most of the nonadherent CD4-CD8- T cells expressed this receptor complex. The adhesion of T cells to bone marrow stroma almost entirely was accounted for by CD49d and CD90, whereas that of adherent CD4-CD8- cells also was dependent on CD44, CD62L, and CD117 receptor. Blocking antibody combinations failed to reduce the adherence of these early T cells to less than 50% that of the control. On the other hand, the adhesion of unselected thymocytes to the stroma was reduced by 80%, using the same blocking antibodies. Therefore, the participation of additional molecules in the adhesion of early T cells to mesenchymal stroma is implicated. Comparison between the interaction of T cells with bone marrow mesenchymal or with thymus-derived epithelial stroma indicated that T cells utilize a selected set of adhesion molecules under each situation. Although CD49d and CD90 participated in both cases, CD11a, CD18, and CD2 receptors played a dominant role in the adhesion of T cells to thymic epithelium only. This study may point to a role of mesenchymal stroma in the regulation of early T-cell lymphopoiesis in the bone marrow.

Loss of lamin A function increases chromatin dynamics in the nuclear interior.

Chromatin is organized in a highly ordered yet dynamic manner in the cell nucleus, but the principles governing this organization remain unclear. Similarly, it is unknown whether, and how, various proteins regulate chromatin motion and as a result influence nuclear organization. Here by studying the dynamics of different genomic regions in the nucleus of live cells, we show that the genome has highly constrained dynamics. Interestingly, depletion of lamin A strikingly alters genome dynamics, inducing a dramatic transition from slow anomalous diffusion to fast and normal diffusion. In contrast, depletion of LAP2α, a protein that interacts with lamin A and chromatin, has no such effect on genome dynamics. We speculate that chromosomal inter-chain interactions formed by lamin A throughout the nucleus contribute to chromatin dynamics, and suggest that the molecular regulation of chromatin diffusion by lamin A in the nuclear interior is critical for the maintenance of genome organization.

SA-1, a nuclear protein encoded by one member of a novel gene family: molecular cloning and detection in hemopoietic organs.

We report the molecular cloning of a novel gene family. The first member of this family was cloned from a mouse lambda gt11 cDNA library using the B92 monoclonal antibody (mAb) raised against stromal cell extracts. This was followed by RACE-PCR using mRNA from the stromal cell line. A 4 kb cDNA was obtained encoding a unique protein sequence of 1258 aa, that we designate stromal antigen (SA)-1. The human SA-1 gene was cloned by homology from a thymus cDNA library and the sequence of the predicted protein was found to be highly homologous to the murine SA-1 (>98.9%). Another cDNA was cloned and the deduced protein (SA-2) was 71% homologous to SA-1. Northern blot and PCR analysis indicated that on the mRNA level the SA-1 gene is expressed in all tissues analyzed and probably encodes a single transcript. The identification of SA-1 protein in tissues and cells required combined immunoprecipitation and Western blotting using a polyclonal antiserum raised against a predicted peptide of SA-1 and the B92 mAb. Using this assay we identified a protein of about 120 kDa in hemopoietic organs. Subcellular fractionation indicated that SA-1 is a nuclear protein. Thus, despite the ubiquitous expression on the mRNA level, the protein was predominantly detected in hemopoietic organs and may therefore be controlled on a post-transcriptional level. The SA-1 gene described in this study is highly conserved between mouse and man. This implies a crucial function for this protein.