A genome-wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

OBJECTIVE: Juvenile rheumatoid arthritis (JRA) represents a heterogeneous group of disorders with a complex genetic component. A genome scan was performed to detect linkage to JRA in 121 families containing 247 affected children in North America (the JRA Affected Sibpair [ASP] Registry). METHODS: Genotype data collected for HLA-DR and 386 microsatellite markers were subjected to multipoint nonparametric linkage analysis. Following analysis of the entire set of families, additional analyses were performed after a priori stratification by disease onset type, age at onset, disease course, and selected HLA-DRB1 alleles. RESULTS: Linkage of JRA to the HLA region was confirmed (logarithm of odds [LOD] score 2.26). Additional evidence supporting linkage of JRA was observed at 1p36 (D1S214; LOD 1.65), 19p13 (D19S216; LOD 1.72), and 20q13 (D20S100; LOD 1.75). For early-onset polyarticular disease, evidence of linkage was found at chromosome 7q11 (D7S502; LOD 3.47). For pauciarticular disease, evidence supporting linkage was observed on chromosome 19p13 (D19S216; LOD 2.98), the same marker that supported linkage to the "JRA" phenotype. Other regions supporting linkage with JRA disease subtype included 20q13, 4q24, 12q24, and Xp11. Stratification of families based on the presence of the HLA-DR8 allele in affected siblings resulted in significant linkage observed at 2p25 (D2S162/D2S305; LOD 6.0). CONCLUSION: These data support the hypothesis that multiple genes, including at least 1 in the HLA region, influence susceptibility to JRA. These findings for JRA are consistent with findings for other autoimmune diseases and support the notion that common genetic regions contribute to an autoimmune phenotype.     

Granulocytic sarcoma manifesting as multiple skeletal lesions

Granulocytic sarcoma is an extramedullary collection of myeloblasts that is usually associated with acute or chronic myeloid leukemia. It can be found in any location throughout the body; however, multifocal skeletal involvement is extremely rare. This report describes a case of granulocytic sarcoma in a 33-year-old man, manifesting as multiple skeletal lesions along with signs of cord compression without any preceding history of myeloid leukemia. Cytogenetic studies revealed t(8,9) translocation, which has never been reported in association with granulocytic sarcoma. The prognostic significance of this finding is unknown. This case report underscores the importance of considering granulocytic sarcoma in the differential diagnosis of spinal tumors, since the tumor may occur before other manifestations of myeloid leukemia are evident.     

Acute blood pressure changes after the onset of atrioventricular nodal reentrant tachycardia: a time-course analysis

INTRODUCTION: We aimed to characterize blood pressure (BP) response at the beginning of atrioventricular nodal reentrant tachycardia (AVNRT) and its relationship to orthostatic challenge and variable atrioventricular interval. METHODS AND RESULTS: In this prospective study of 17 consecutive patients with documented AVNRT, mean BP was analyzed in the supine and upright positions during sinus rhythm, AVNRT, and pacing with atrioventricular delay of 150 msec (AV150) and 0 msec (AV0). Mean BPs were compared at 3-5 seconds, 8-10 seconds, and 28-30 seconds after the onset of AVNRT or pacing. BP decreased immediately after AVNRT initiation, with gradual recovery during the first 30 seconds from 71.9 +/- 16.5 mmHg to 86 +/- 13.8 mmHg, P < 0.01. A similar pattern was observed during AV0, but not during AV150, pacing. While supine, mean BP decrease was more pronounced during AVNRT and AV0 pacing (-26.1% and -32.1%, respectively) than during AV150 pacing (-8%, P = 0.02 and P = 0.07, respectively). This difference subsided 30 seconds after the onset of AVNRT or pacing. When upright, the mean BP time course was similar, but mean BP recovery during AVNRT was slower, and the difference between mean BP during AVNRT and AV150 persisted at 30 seconds. CONCLUSIONS: The initial mean BP decrease during AVNRT recovered gradually within 30 seconds. A short atrioventricular interval is associated with a greater mean BP decrease at the onset of tachycardia. These observations may explain clinical symptoms immediately after the onset of AVNRT.     

Bone mineral density in Iranian patients with inflammatory bowel disease

Patients with inflammatory bowel disease (IBD) are at increased risk of developing osteopenia and osteoporosis. The aim of the study was to investigate the prevalence of decreased bone density and related risk factors in Iranian IBD patients. A total of 126 ulcerative colitis (UC) and 39 Crohn’s disease (CD) patients were enrolled. Dual-energy x-ray absorptiometry technique was used to measure bone density, and blood samples were obtained to measure biochemical markers. To find predictive variables for bone mineral density (BMD), stepwise regression analysis was carried out. A total of 53 IBD patients (32.1%) had diminished bone mineral density at either lumbar spine (L1–L4) or femoral neck. Of these, 9 (5.4%) had osteoporosis; however, 44 (26.7%) were osteopenic. Femoral neck bone density was significantly decreased among CD patients (p<0.04). There was no significant difference in BMD between men and women. We have found significant differences in BMD T scores at lumbar L1–L4, L2–L4, and femoral neck in corticosteroid ever-users (p<0.002, p<0.001, p<0.003, respectively). There was no significant difference in biochemical markers between UC and CD patients, except that more CD patients were hypocalcemic (p<0.001). Stepwise regression analysis has revealed lumbar spine T score was predicted by age (p<0.0001), corticosteroid use (p<0.002), and body mass index (BMI) (p<0.005); however, femoral neck was predicted by age (p<0.0001), BMI (p<0.0001), smoking (p<0.009), and corticosteroid use (p<0.028). Low bone density in Iranian UC and CD patients is in accordance with Western societies. Treatment with corticosteroid has increased this possibility in both groups. Corticosteroid use, age, smoking, and BMI are predictive factors for low bone density.     

Intra- and interatrial conduction abnormalities: hemodynamic and arrhythmic significance

Background

Rigid time-based dosing protocol(s) currently used in the clinic for cryoballoon ablation of atrial fibrillation may be inadequate to guide the circumferential and transmural cryothermal energy transfer across the pulmonary vein (PV) and may result in injury to collateral tissues or electrical gaps between the PV and left atrium (LA).

Objective

A physiologic endpoint (e.g., acute time-to-PV isolation a.k.a. time-to-effect; TTE) may be effective in the determination of a transmural lesion formation and may allow for individualized ablation dosing across each PV.

Methods

Thirty PVs from 15 dogs were randomized into five dosing protocols, including (1) TTE?+?60 s, (2) TTE?+?90 s, (3) TTE?+?120 s, (4) TTE?+?150 s, and (5) 2?×?180 s. Ablations were conducted with a 23-mm second-generation cryoballoon, and TTE was assessed during a freeze by pacing from an inner balloon-lumen circular diagnostic catheter to a quadripolar diagnostic catheter in the coronary sinus. After ablation, animals were survived for 30 to 34 days, and repeat electrophysiology assessment of PV isolation was conducted after which animals were euthanized for gross anatomy and histological examination.

Results

At study termination, efficacy endpoint evaluations were based on maintenance of PV electrical isolation, gross anatomy assessment of PV lesions, and histological examination of PVs. Five efficacy endpoint failures were noted, including the following: 1 PV in the TTE?+?90 sec group; 2 PVs in the TTE?+?120 sec group; 1 PV in the TTE?+?150 s group; and 1 PV in the 2?×?180 s group. Regarding safety, one phrenic nerve injury was observed in the 2?×?180 s cohort. No other complications were observed.

Conclusions

In a canine model, effective PV isolation could be found even in the shortest duration dosing cohort (TTE?+?60 s). One complication (phrenic nerve injury) was observed in the longest duration dosing group (2?×?180 s). Further studies will be required to correlate these results to a 28-mm cryoballoon (more commonly used in the cryoablation of a human LA); however, to date, this is the first reporting of a successful cryoablation using TTE?+?60 s dosing (approximately 90 s total duration of freezing).

     

A Review of Different Aspects of Applying Asphalt and Bituminous Mixes under a Railway Track

Asphalt is a common material that is used extensively for roadways. Furthermore, bituminous mixes have been used in railways, both as asphalt and as mortar. Different agencies and research institutes have investigated and suggested various applications. These studies indicate the benefits of bituminous material under railways, such as improving a substructure’s stiffness and bearing capacity; enhancing its dynamic characteristics and response, especially under high-speed train loads; waterproofing the subgrade; protecting the top layers against fine contamination. These potential applications can improve the overall track structure performance and lead to minimizing settlement under heavy loads. They can also guarantee an appropriate response under high-speed loads, especially in comparison to a rigid slab track. This review paper documents the literature related to the utilization of asphalt and bituminous mixes in railway tracks. This paper presents a critical review of the research in the application of asphalt and bituminous mixes in railway tracks. Additionally, this paper reviews the design and construction recommendations and procedures for asphalt and bituminous mixes in railway tracks as practiced in different countries. This paper also provides case studies of projects where asphalt and bituminous mixes have been utilized in railway tracks. It is anticipated that this review paper will facilitate (1) the exchange of ideas and innovations in the area of the design and construction of railway tracks and (2) the development of unified standards for the design and construction of railway tracks with asphalt and bituminous mixtures.     

Elevated serum nitric oxide and hydrogen peroxide levels as potential valuable predictors of herpes zoster

Objective: To evaluate the biomarkers of oxidative stress in herpes zoster patients compared with control subjects.Methods: This study compared the nitric oxide(NO),hydrogen peroxide(H_2 O_2),malon dialdehyde,uric acid,and bilirubin levels between 43 herpes zoster patients and 47 age-matched control subjects.The area under the curve of the receiver operating characteristic curve was performed to evaluate the final logistic regression model.Results: The significant differences were observed in the serum levels of NO,H_2 O_2,and malondialdehyde between the case and the control groups(P0.001).However,no statistical differences were found in both uricacid and bilirubin levels between the groups.Additionally,the raised oxidant biomarkers were strongly associated with increased disease severity(P0.001).Multiple logistic regression analysis with the highest area under the curve [0.98(95% CI 0.95-1.00)]and the minimum number of variables showed that high levels of NO(OR 1.24; 95% CI 1.06-1.46; P=0.008) and H_2 O_2(OR 1.25; 95% CI 1.09-1.43; P=0.001) were associated with herpes zoster.Conclusions: High levels of NO and H_2 O_2 were observed in patients with herpes zoster.Increased NO and H_2 O_2 levels might be associated with herpes zoster,which needs to be confirmed by further studies.     

Machine‐learning algorithms for predicting hospital re‐admissions in sickle cell disease

Reducing preventable hospital re‐admissions in Sickle Cell Disease (SCD) could potentially improve outcomes and decrease healthcare costs. In a retrospective study of electronic health records, we hypothesized Machine‐Learning (ML) algorithms may outperform standard re‐admission scoring systems (LACE and HOSPITAL indices). Participants (n = 446) included patients with SCD with at least one unplanned inpatient encounter between January 1, 2013, and November 1, 2018. Patients were randomly partitioned into training and testing groups. Unplanned hospital admissions (n = 3299) were stratified to training and testing samples. Potential predictors (n = 486), measured from the last unplanned inpatient discharge to the current unplanned inpatient visit, were obtained via both data‐driven methods and clinical knowledge. Three standard ML algorithms, Logistic Regression (LR), Support‐Vector Machine (SVM), and Random Forest (RF) were applied. Prediction performance was assessed using the C‐statistic, sensitivity, and specificity. In addition, we reported the most important predictors in our best models. In this dataset, ML algorithms outperformed LACE [C‐statistic 0·6, 95% Confidence Interval (CI) 0·57–0·64] and HOSPITAL (C‐statistic 0·69, 95% CI 0·66–0·72), with the RF (C‐statistic 0·77, 95% CI 0·73–0·79) and LR (C‐statistic 0·77, 95% CI 0·73–0·8) performing the best. ML algorithms can be powerful tools in predicting re‐admission in high‐risk patient groups.     

Neuroprotective effects of coenzyme Q10 in Parkinson's model via a novel Q10/miR-149-5p/MMPs pathway

Parkinson's disease (PD) is a complex neurodegenerative disease in which the understanding of the underlying molecular mechanisms can be constructive in the diagnosis and treatment. Matrix metalloproteinase (MMPs) elevation and damage to the blood–brain barrier (BBB) are critical mechanisms involved in the PD separation. Studies have revealed that changes in miR-149-5p and CoQ10 are associated with BBB damage, and CoQ10 can affect the levels of some miRs. Hence, in the present study, we aimed to evaluate CoQ10 and miR-149-5p mimic on miR-149-5p, MMPs and TH expression, and behavioral functions of the PD models. PD was induced by injection of 6-OHDA into the rats' Medial Forbrain Bundle (MFB). The behavioral tests, including the Rotation test, Rotarod test, and Open field test, have been directed two weeks after PD induction. Next, the MiR-149-5p mimic (miR-mimic) and CoQ10 have been administered to rats. The same behavioral tests have been evaluated two weeks after administration to investigate the effect of miR-149-5p mimic and CoQ10. The rats were followed extra four weeks, and the behavioral tests have performed again. Finally, the expression of MMPs and miR-149-5p genes was measured using RT-qPCR, and tyrosine hydroxylase (TH) was assessed through immunohistochemistry analysis. According to the obtained results, the level of miR-149-5p has decreased, followed by PD induction in rats. RT-qPCR analysis has represented upregulation and downregulation of miR-149-5p and MMP-2,9, respectively, after miR-mimic and CoQ10 treatment. The treated rats have also represented improved motor function and increased TH?+ ?cells in the striatum according to the behavioral tests and immunohistochemistry assay. Taking together miR-149 and CoQ10 has shown to have an impressive potential to prevent damage to dopaminergic neurons caused by 6-OHDA injection through reducing MMP-2,9, increased TH expression, and improved motor function.

     

Steroid C-20 oxidoreductase activity of duck intestinal mucosa: the interrelations of the enzymatic activity with steroid binding

The binding of corticosterone and aldosterone to domestic duck (Anas platyrhynchos)-dispersed colonic mucosal cells at 37 degrees was investigated. It was found that in contrast to experiments using cell-free intestinal preparations, corticosterone was extensively metabolized and it was the metabolite, not the native steroid that became receptor bound and all the bound ligand was in the nuclear fraction. The metabolite turned out to be identical with 4-pregnene-11 beta,20 beta, 21-triol-3-one (20 beta-dihydrocorticosterone, 20 beta-DHB). Binding experiments with [3H]corticosterone yielded the following kinetic parameters: Kd = 87.6 nM, Nmax = 337,900 sites/cell. When synthetic [3H]20 beta-DHB was used as the ligand a curvilinear-binding isotherm was obtained. This could be resolved into a high affinity-low capacity (HA) and a low affinity-high capacity (LA) component with the following binding parameters: Kd,HA = 91 nM, Nmax,HA = 130,800 sites/cell; Kd,LA = 5.4 x 10(-6) M, Nmax, LA = 3.7 x 10(6) sites/cell. Binding of the metabolite to cell-free preparations, at 0 degree, gave the following results: for cytosol, linear-binding isotherm, Kd = 14.0 nM, Nmax = 26.5 fmol/mg protein; and for crude nuclei, curvilinear-binding isotherm, Kd,HA = 45.0 nM, Nmax, HA = 5.33 pmol/mg DNA; Kd,LA = 2.2 x 10(-6) M, Nmax,LA = 286.6 pmol/mg DNA. [3H]Aldosterone was also bound by the dispersed whole cells and again, this binding was only nuclear (Kd = 9.3 nM, Nmax = 10,042 sites/cell). The bound ligand was unchanged aldosterone. Competition experiments have shown that aldosterone did not compete with 20 beta-DHB for binding sites and vice versa. The intracellular 20 beta-hydroxysteroid oxidoreductase responsible for the transformation of corticosterone was found mostly in the cytoplasm. Kinetic studies with the enzyme yielded classical Michaelis-Menten kinetics (Km = 15.7 microM, Vmax = 2.6 nmol/min/mg protein). The enzyme had an apparent Mr of 35 kDa and a Rs of 25.5 A. It is believed that our results might explain the binding of aldosterone to mineralocorticoid-binding sites in the presence of overwhelming concentrations of corticosterone and that experiments with cell-free tissue preparations, performed at 0 degree, do not reflect the true cellular-binding events.