Search

We have developed a Triangular Spatial Relationship (TSR)-based computational method for protein structure comparison and motif discovery that is both sequence and structure alignment-free. A protein 3D structure is modeled by all possible triangles that are constructed with every three C α atoms of amino acids as vertices. Every triangle is represented using an integer (a key). The keys are calculated by a rule-based formula which is a function of a representative length, a representative angle, and the vertex labels associated with amino acids. A 3D structure is thereby represented by a vector of integers (TSR keys). Global or local structure comparisons are achieved by computing all keys or a set of keys, respectively. Many enzymatic reactions and notable marketed drugs are highly stereospecific. Thus, in this paper, we propose a modified key calculation formula by including a mechanism for discriminating mirror-image keys to capture stereo geometry. We assign a positive or a negative sign to the integers representing mirror-image keys. Applying the new key calculation function provides the ability to further discriminate mirror-image keys that were previously considered identical. As the result, applying the mirror-image discrimination capability (i) significantly increases the number of distinct keys; (ii) decreases the number of common keys; (iii) decreases structural similarity; (iv) increases the opportunity to identify specific keys for each type of the receptors. The specific keys identified in this study for the cases of without (not applying) and with (applying) mirror-image discrimination can be considered as the structure signatures that exclusively belong to a certain type of receptors. Applying mirror-image discrimination introduces stereospecificity to keys for allowing more precise modeling of ligand - target interactions. The development of mirror-image TSR keys of C α atom, in conjunction with the integration of C α TSR keys with all-atom TSR keys for amino acids and drugs, will lead to a new and promising computational method for aiding drug design and discovery., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Asthma is associated with increased risk of cardiovascular diseases. Despite many presenting with symptoms of asthma, asthma cannot always be confirmed by physiological assessment. It is thus far unknown if the heightened cardiovascular risk applies to this group. The purpose of this study was to examine markers of cardiovascular risk, including endothelial function, arterial stiffness, and systemic inflammation, in individuals with confirmed asthma, unconfirmed asthma, and healthy controls. As short-acting beta agonist (SABA) use is associated with increased cardiovascular risk, a secondary analysis was conducted to investigate the impact of regular SABA use on vascular outcomes., Methods: Individuals with confirmed asthma (n = 26), unconfirmed asthma (n = 15), and healthy controls (n = 26) were recruited for this cross-sectional study. Asthma was confirmed by FEV 1 reversibility, methacholine challenge, or exercise challenge. Endothelial function was assessed using flow-mediated dilation (FMD), arterial stiffness using pulse wave velocity (PWV), and systemic inflammation by C-reactive protein (CRP) levels., Results: FMD was significantly lower in both asthma groups compared to controls (confirmed: 7.7 ± 3.6%, unconfirmed: 7.3 ± 3.5%, controls: 10.4 ± 3.6%, p = 0.02). No difference was found in PWV nor CRP. Asthma participants who used SABA had increased arterial stiffness compared to those without SABA (9.2 ± 2.7 m/s, 7.7 ± 1.1 m/s respectively, p = 0.03). No difference was seen in FMD or CRP between SABA groups., Conclusion: Individuals with a clinical history of asthma symptoms demonstrate vascular impairments regardless of physiological confirmation of disease. Regular SABA use increases arterial stiffness. Avoiding potentially inappropriate SABA use among people without physiologically confirmed asthma may thus be beneficial in curbing cardiovascular risk., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Asthmatics are at increased cardiovascular disease risk, which has been linked to beta2(β 2 )-agonist use. Inhalation of β 2 -agonists increases sympathetic nerve activity (SNA) in healthy individuals, however the systemic impact of salbutamol in asthmatics using β 2 -agonists regularly is unknown., Objectives: This study compared the systemic vascular responses to a clinical dose of salbutamol (Phase I) and following an acute increase in SNA (Phase II) in asthmatics and controls., Methods: Fourteen controls and 14 asthmatics were recruited for Phase I. On separate days, flow-mediated dilation (FMD) and peripheral arterial stiffness (pPWV) were evaluated at baseline and following either 400 μg inhaled salbutamol or a placebo inhaler. For Phase II, heart rate, blood pressure, vascular conductance, pPWV, and central (c)PWV were evaluated in response to a large increase in SNA brought on by cold-water hand immersion (i.e. cold-pressor test) or body-temperature water hand immersion (i.e. control) in 10 controls and 10 asthmatics., Results: Following salbutamol, asthmatics demonstrated reduced FMD (-3.0%, p < 0.05) and increased pPWV (+0.7 m/s, p < 0.05); however, salbutamol had no effect in controls. The cold-pressor test resulted in similar increases in blood pressure, vascular flow rates and conductance, pPWV, and cPWV in both asthmatics and controls, suggesting similar neurovascular transduction in asthmatics and controls., Conclusion: Inhaled Salbutamol leads to increased arterial stiffness and reduced FMD in asthmatics. As asthmatics and controls had similar vascular responses to an increase in SNA, these findings suggest asthmatics have heightened sympathetic responses to β 2 -agonists which may contribute to the increased cardiovascular risk in asthma., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Heightened arterial stiffness is a marker of cardiovascular risk and is elevated in chronic obstructive pulmonary disease (COPD). Physical activity has been shown to reduce arterial stiffness, and our previous work has shown that arterial stiffness is related to physical activity and exercise tolerance in COPD. The purpose of this study was to evaluate whether baseline physical activity and exercise tolerance influence the cardiovascular benefits associated with standard COPD outpatient pulmonary rehabilitation (PR)., Methods: A total of 66 patients with COPD were recruited from the G.F. MacDonald Centre for Lung Health, Edmonton, Alberta, prior to entering PR. Another 23 COPD patients not attending the PR program were recruited as time controls (TC). Arterial stiffness (carotid-radial pulse wave velocity, PWV), physical activity (steps taken over three days), and 6-min walk distance (6MWD) were assessed before and after PR, or before and after six weeks of standard care., Results: Thirty-nine PR and 11 TC completed all parts of the study. Following PR, there was no overall change in PWV. However, changes in arterial stiffness with PR were dependent on baseline exercise tolerance, with those patients with a 6MWD <350 m showing a significant reduction in PWV following PR (6MWD >350 m: 8.2 ± 1.6 to 8.5 ± 1.7 versus 6MWD <350 m: 9.2 ± 0.6 to 7.3 ± 2.0 m/s, p < 0.05). The PWV response to PR was not influenced by baseline physical activity levels., Conclusion: COPD patients with low exercise tolerance appear to derive the greatest cardiovascular benefits from PR., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Food allergy is an adverse immune reaction that occurs reproducibly on exposure to a given food. Prevalence rates of food allergy continue to increase worldwide, sparking continual research efforts in finding a suitable and safe cure. Food avoidance, the current standard of care, can be difficult to achieve. This review aims to provide a broad overview of immunoglobulin E-mediated food allergy, highlighting its epidemiology, masqueraders, immunopathophysiology, clinical presentation, diagnostic work-up and available preventative and treatment strategies. This review also discusses novel, investigative therapies that offer promising therapeutic options, yet require continued research efforts to determine safety effects. Inducing tolerance, whether by immunotherapy or by the administration of monoclonal antibodies, allows us to move toward a cure for food allergy, which could vastly change this field of allergic diseases in the coming decades., (Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Renal cell carcinoma (RCC) is a common malignancy following kidney transplantation. We describe RCC risk and examine RCC risk factors among US kidney recipients (1987-2010). The Transplant Cancer Match Study links the US transplant registry with 15 cancer registries. Standardized incidence ratios (SIRs) were used to compare RCC risk (overall and for clear cell [ccRCC] and papillary subtypes) to the general population. Associations with risk factors were assessed using Cox models. We identified 683 RCCs among 116 208 kidney recipients. RCC risk was substantially elevated compared with the general population (SIR 5.68, 95% confidence interval 5.27-6.13), especially for papillary RCC (SIR 13.3 versus 3.98 for ccRCC). Among kidney recipients, RCC risk was significantly elevated for blacks compared to whites (hazard ratio [HR] 1.50) and lower in females than males (HR 0.56). RCC risk increased with prolonged dialysis preceding transplantation (p-trend < 0.0001). Risk was variably associated for RCC subtypes with some medical conditions that were indications for transplantation: ccRCC risk was reduced with polycystic kidney disease (HR 0.54), and papillary RCC was increased with hypertensive nephrosclerosis (HR 2.02) and vascular diseases (HR 1.86). In conclusion, kidney recipients experience substantially elevated risk of RCC, especially for papillary RCC, and multiple factors contribute to these cancers., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

This case report presents a patient suffering acute fatal intracranial-intratumoral hemorrhage during a gamma knife treatment session. Acute hemorrhage during a radiosurgery session is extremely rare and a plausible cause for this case is discussed along with a literature review of previously reported incidents. The patient was a 71-year-old male presenting with three large intracranial lesions and an underlying primary renal cell carcinoma malignancy. Because of a severe kyphotic deformity resulting from ankylosing spondylitis, the patient was placed in a moderate Trendelenburg position to allow his head to fit into the gamma knife unit during the radiosurgery session. The two left-sided lesions were to be treated with 20 Gy to the 50% isodose line, and the right-sided lesion with 16 Gy to the 40% isodose line. Anesthesia was available throughout the treatment session to aid with pain control. The gamma knife treatment was aborted because the patient suffered a generalized seizure while in the unit. Immediate head CT of the patient revealed large acute hemorrhages into all three intracranial masses. This proved to be a fatal complication. It is likely that this positioning contributed to the hemorrhage. The clinical history of this patient is provided as well as a review of the literature on acute intracranial hemorrhage associated with radiosurgical therapy.

Previous studies have suggested that susceptibility to arsenic toxicity could be influenced by micronutrients, in particular selenium, methionine, and beta-carotene. A case-control study was conducted in West Bengal, India, in a region known to have groundwater arsenic contamination, to determine whether differences in micronutrient status contribute to susceptibility to arsenic-induced skin lesions. Micronutrient status was assessed by blood levels of specific micronutrients and metabolic indicators. Blood was obtained from 180 cases with skin lesions and 192 controls. Blood assays measured micronutrients and carotenoids (folate, selenium, vitamin B12, vitamin B6, retinol, alpha-tocopherol, lutein/zeaxanthin, beta-carotene, lycopene, beta-cryptoxanthin) and metabolic indicators such as glucose, cholesterol, transthyretin, amino acids, and proteins potentially associated with methylation (cysteine, homocysteine, methionine, glutathione). The distributions of nutrient concentrations were similar in cases and controls. The median selenium concentrations in cases and controls were both 1.15 micromol/L, and there was little evidence of differences in other micronutrients. Odds ratios (ORs) for arsenic-induced skin lesions were estimated for each quartile of nutrient concentrations, using the quartile with the highest nutrient level as the referent group. There were no clear trends associated with deficiencies of any micronutrient or metabolic indicator. For decreasing quartiles of selenium, the OR estimates were 1.00, 0.67, 0.99, 0.80; P=0.81; for methionine, the OR estimates were 1.00, 0.83, 0.78, 0.72; P=0.29. For beta-carotene, the ORs were 1.00, 0.53, 0.51, 0.96, demonstrating no increased risk at the lower quartiles. The measured micronutrients and metabolic indicators investigated do not appear to modify the risk of developing arsenic-induced skin lesions. The lack of any trend of increasing risk with lower selenium, vitamin E, and beta-carotene concentrations has important implications for proposed therapeutic interventions. The emphasis of interventions should be on reducing arsenic exposure.

Objective: We tested the hypothesis that the inadequately perfused placenta increases production of leptin, which can be detected in maternal serum., Study Design: Sprague-Dawley rats (n=13), on day 14 of gestation, had placement of clips on the aorta and the ovarian arteries providing 35 per cent occlusion of the vessels. Eight rats had sham surgery and 14 rats served as non-surgical controls. All animals were sacrificed on day 19 of gestation. Maternal serum was obtained, and pups and placentae were weighed., Results: Both placental weights and pup weights were reduced due to reduced uterine perfusion and were negatively correlated with maternal serum leptin (P=0.018 and 0.028, respectively). Maternal serum leptin was increased in the treatment group (2.21 ng/ml+/-64 ng/ml) compared to controls (1.66 ng/ml+/-38 ng/ml) (P=0.031)., Conclusions: Our findings suggest that reduced placental perfusion results in an increase in maternal serum leptin. Further investigation is needed to determine if maternal serum leptin may be useful in identifying pregnancies with uteroplacental insufficiency.

The purpose of this study was to investigate methods for ascertaining arsenic exposure for use in biomarker studies. Urinary arsenic concentration is considered a good measure of recent arsenic exposure and is commonly used to monitor exposure in environmental and occupational settings. However, measurements reflect exposure only in the last few days. To cover longer time periods exposure can be estimated using arsenic intake data, calculated by combining measures of environmental arsenic and inhalation/ingestion rates. We compared these different exposure assessment approaches in a population chronically exposed to arsenic in drinking water in northern Chile. The study group consisted of 232 people, some drinking water low in arsenic (15 micrograms/l) and others drinking water with high arsenic concentrations (up to 670 micrograms/l). First morning urine samples and questionnaire data, including fluid intake information, were collected from all participants. Exfoliated bladder cells were collected from male participants for the bladder cell micronuclei assay. Eight different indices of exposure were generated, six based on urinary arsenic (microgram As/l urine; microgram As/g creatinine; microgram InAs/l urine; microgram MMA/l urine; microgram DMA/l urine; microgram As/h, excreted), and two on fluid intake data (microgram As/day, ingested; microgram As/l fluid ingested-day). The relationship between the different exposure indices was explored using correlation analysis. In men, exposure indices were also related to a biomarker of effect, bladder cell micronuclei. While creatinine-adjusted urinary arsenic concentrations had the strongest correlations with the two intake estimates (r = 0.76, r = 0.81), unadjusted urinary arsenic showed the strongest relationship with bladder cell micronuclei. These data suggest that, in the case of the bladder, unadjusted urinary arsenic concentrations better reflect the effective target organ dose compared to other exposure measures for biomarker studies.

Venous air embolism (VAE) can be a lethal complication of surgical procedures, during which (1) venous pressure at the site of surgery is subatmospheric or (2) gas is forced under pressure into a body cavity. Though classically associated with neurosurgery, VAE is also a potential complication of laparoscopic, pelvic, and orthopedic procedures. It is, therefore, essential for the practicing anesthesiologist to recognize and treat venous air entrainment. An in-depth review of the pathophysiology, clinical presentation, detection, prevention, and treatment of VAE is presented.

The micronucleus (MN) assay in human exfoliated cells has been widely used to detect the genotoxic effects of environmental mutagens, infectious agents and hereditary diseases. Substantial variability characterizes the MN frequencies reported by different research groups. One reason for this may be the restricted resolution power of the Feulgen-Fast-Green staining that is routinely used. Here we describe a new version of the MN assay that employs fluorescent propidium iodide staining along with fluorescence in situ hybridization (FISH) with a centromeric probe. Buccal and urothelial cells were collected from 5 healthy unexposed female volunteers and 55,000 cells analyzed for MN frequency and abnormal nuclear events. The Feulgen-Fast-Green and the new fluorescent staining produced very similar results. The frequency of MN in buccal cells was 0.145 +/- 0.118% and in urothelial cells 0.083 +/- 0.074%. No correlation was found between the frequencies of MN in the two types of exfoliated cells. FISH with a centromeric probe allowed MN containing whole chromosomes with a centromere to be differentiated from those containing only acentric fragments. The former appear as a result of chromosome lagging in mitosis, while those without a centromere are due to chromosome breakage. In urothelial cells 43% of MN were centromere-negative and in buccal cells -44%. Fluorescent staining provided more accurate scoring of degenerative cells than standard Feulgen-Fast-Green staining. The combined frequency of pycnotic cells, "broken eggs" and cells with fragmented nuclei did not exceed 2%, while that of karyorrhexis and karyolysis together was as high as 21%. Significant interindividual variability was found in the frequency of cells with karyolysis and karyorrhexis. Thus, the new version of micronucleus assay allows for MN to be scored more precisely, the mechanism of MN formation to be determined and abnormal nuclear events to be readily identified in exfoliated human cells. It is therefore ideal for studying genotoxicity in human populations using exfoliated cells from the mouth, bladder and nose.