The blood level of thioredoxin 1 as a supporting biomarker in the detection of breast cancer

Background There is a long-time unmet need for a means to detect breast cancer (BC) using blood. Although mammography is accepted as the gold standard for screening, a blood-based diagnostic can complement mammography and assist in the accurate detection of BC in the diagnostic process period of early diagnosis. We have previously reported the possible use of thioredoxin 1 (Trx1) in serum as a novel means to detect BC. In the present study, we validated the clinical utility of Trx1 to identify BC by testing sera from biopsy-confirmed cancer patients and women without cancer. Methods We have generated monoclonal antibodies against Trx1 and developed an ELISA kit that can quantitate Trx1 in sera. The level of Trx1 was determined in each serum from women without cancer (n = 114), as well as in serum from patients with BC (n = 106) and other types of cancers (n = 74), including cervical, lung, stomach, colorectal, and thyroid cancer. The sera from BC patients were collected and classified by the subjects’ age and cancer stage. In addition to the Trx1 levels of BC patients, several pathological and molecular aspects of BC were analyzed. Test results were retrospectively compared to those from mammography. Each test was duplicated, and test results were analyzed by ROC analysis, one-way ANOVA tests, and unpaired t-tests. Results The mean level of Trx1 from women without cancer was 5.45 ± 4.16 (±SD) ng/ml, that of the other malignant cancer patient group was 2.70 ± 2.01 ng/ml, and that from the BC group was 21.96 ± 6.79 ng/ml. The difference among these values was large enough to distinguish BC sera from non-BC control sera with a sensitivity of 97.17% and specificity of 94.15% (AUC 0.990, p < 0.0001). Most Trx1 levels from BC patients’ sera were higher than the cut-off value of 11.4 ng/ml regardless of age, stage, histological grade, type, and specific receptors’ expression profile of BC. The level of Trx1 could rescue women from most cases of misread or incomplete mammography diagnoses. Conclusion These results indicated that the blood level of Trx1 could be an effective and accurate means to assist the detection of BC during the early diagnosis period.

Continuous Renal Replacement Therapy Using Membranes with Increased Adsorption Capacity in Patients with Septic Shock after Neurosurgical Interventions

Introduction. The combination of primary brain injury with cytokine storm and hemodynamic disturbance in septic shock leads to secondary brain damage and growing neurological deficit. Blood purification procedures can be considered as an additional option in the treatment of septic shock in this group of patients.Subjects and Methods. The study included 11 patients after neurosurgical interventions with septic shock and acute kidney injury who underwent continuous renal replacement therapy (CRRT) using membranes with increased adsorption capacity.Results. During CRRT there was a significant regression in severity of multiorgan dysfunction according to SOFA score, a decrease in the requirement for vasopressor support with norepinephrine, and a decrease in lactate blood level. In addition, after the end of the procedure, there was a significant decrease in procalcitonin blood level. Septic shock reversal was observed in 8/11 patients (72.7%). In 3/11 patients, neurological deficits regressed during the procedure.Conclusions. The results indicate the possibility of using CRRT with membranes with increased adsorption capacity in patients after neurosurgical interventions with septic shock. Changes in neurological status can be considered as an additional parameter for the effectiveness of therapy for septic shock in patients with primary brain injury.

Association of Circulating Circular RNAs (mmu-015947, hg38-0008980, and DLGAP4) in Diagnosis, Diseases Severity, and Prognosis of Ischemic Stroke

Backgrounds Quickly diagnosing ischemic stroke (IS) is a critical issue in clinical studies, as it allows more effective therapy and stops the progression of IS. The blood level of CircRNAs after stroke may act as a rapid diagnostic marker.Methods and Results In this study, the blood level of circRNAs was evaluated using a real-time PCR. We used logistic and linear regression analysis to evaluate the potential of circRNAs levels with the risk of IS. Circ-mmu-015947 was up-regulated in patients. Its expression also showed a good value in predicting IS risk, and a significant diagnostic value. CircDLGAP4 was decreased in patients compared with controls and logistic regression showed its expression negatively associated with IS risk. The expression level of hg38 was reduced significantly in patients with small vessel disease (SVD) and the linear regression analysis showed a negative relationship between hg38 expression with SVD subtype. Circhg38 expression relative to controls showed a significant association with IS risk. Conclusion Taken together, circulating circ-mmu-015947 may serve as a novel biomarker for IS, and we found a significant decrease in the level of hg38-0008980 after IS it may act as a novel circRNA in IS pathophysiology with a positive correlation with stroke severity.

Higher teicoplanin blood level needed in elderly critically ill patients

Background: Significant changes in the pathophysiology of older critically ill patients may affect the pharmacokinetics and pharmacodynamics of teicoplanin. This study aimed to determine the optimal teicoplanin blood level in this patient population. Materials & Methods: 128 older critically ill and 86 older non-critically ill patients were involved and analyzed. Results: The target thresholds of teicoplanin blood concentrations in older critically ill patients and non-critically ill patients should be 31.4mg/L and 15.3mg/L, respectively. The dose of teicoplanin in older critically ill patients should be greater than 800 mg to achieve the target blood level. Conclusion : An individualized dosing approach of teicoplanin based on therapeutic drug monitoring is necessary for older critically ill patients.

Role of Bifidobacterium spp. intake in improving depressive mood and well-being and its link to kynurenine blood level: an interventional study

Objectives Evidence for the contribution of the brain-gut-microbiota axis to the depression pathophysiology is increasing nowadays. Disturbed gut microbiota equilibrium along with bad dietary habits both lead to kynurenine pathway abnormalities contributing to the depression pathophysiology. In this respect, many studies are found but the interventional clinical trials are limited. The present interventional study aims to evaluate the impact of Bifidobacterium spp. supplementation together with improving dietary intake on depressive mood and well-being and their correlation with kynurenine blood level in adult Egyptian healthy volunteers. Methods A number of 98 healthy female volunteers with a mean age of 46.96 ± 1.82 years were selected and enrolled in this study. They were given yogurt enriched with Bifidobacterium spp. daily for eight weeks. Clinical examination as well as questionnaires for the evaluation of psychological well-being and depression were done at base line and after eight weeks of intervention. Fasting blood samples and stool samples were collected from all subjects at baseline and eight weeks after the intervention for the investigation of serum kynurenine concentration, blood hemoglobin, serum transaminases (ALT & AST) serum urea and creatinine as well as fecal Bifidobacterium count. Results Data revealed that both depression and well-being showed highly significant improvement combined with significant drop in kynurenine blood level after intervention. Also, a significant rise in fecal Bifidobacterium count and a significant improvement in hemoglobin level and activity of liver enzymes were recorded. After intervention, a significant negative correlation was recorded between depression and fecal Bifidobacterium count as well as between serum kynurenine level, and well-being. Conclusion Bifidobacterium spp. supplementation combined with improvement in dietary intake resulted in improvement of depressive mood and well-being and reduced kynurenine blood level.

Primary hypothyroidism as a predictor of the hypogonadism development

Background. Human lifestyle significantly affects human health and reproductive functions. The presence of hypothyroidism negatively impacts the health, activity, and reproductive status. This study was aimed to assess hormonal status, metabolic and anthropometric parameters in men of active reproductive age with primary hypothyroidism. Materials and methods. Totally 60 males with primary hypothyroidism were included in the study. A comparative analysis of hormonal, anthropometric, and metabolic para­meters in 60 men with hypothyroidism (basic group) and 25 men wi­thout hypothyroidism and other chronic somatic diseases (control group) was performed. The mean age of the subjects was 42.4 ± 2.7 years. Results. It has been established that hypothyroidism was accompanied by an increase in serum concentrations of cholesterol and low-density lipoprotein cholesterol in comparison with control group (25 men without hypothyroidism) indicating metabolic disturbance. The data shows the significant effect of hypothyroidism on testosterone and follicle-stimulating hormone (FSH) serum concentration but not on luteinizing hormone, estradiol levels. Patients with hypothyroidism had lower circulating testosterone and higher FSH level in comparison with the controls. The reproductive hormone changes in men with hypothyroidism can result in deleterious effects on sexual functions including erectile dysfunction, reduced libido, and alteration in spermatogenesis. Conclusions. In men with hypothyroidism, changes in hormonal status have been found, which manifested in a decrease in testosterone and an increase in the blood level of follicle-stimulating hormone. The effect of hypothyroidism on the blood level of other hormones (luteini­zing, estradiol, cortisol) has not been established. Hypothyroidism in men is accompanied by changes in lipid metabolism (increased levels of total cholesterol and low-density lipoprotein cholesterol).

Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

Identification of diabetic nephropathy in patients undergoing kidney biopsy through blood and urinary profiles of D-serine

Background: The diagnosis of diabetic nephropathy (DN), the major cause of end-stage kidney disease, requires kidney biopsy. D-Serine, present only in trace amounts in humans, is a biomarker for kidney diseases and shows its potential to distinguish the origin of kidney diseases, whose diagnoses usually require kidney biopsy. We extended this concept and examined the potential of D-serine in the diagnosis of DN. Methods: Patients with biopsy-proven DN, primary glomerulonephritis (minimal change disease and IgA nephropathy), and participants without kidney disease, were enrolled. A total of 388 participants was included in this study, and levels of D-serine in blood and urine were measured using two-dimensional high-performance liquid chromatography, and urinary fractional excretion (FE) of D-serine was calculated. Utilizing data from 259 participants, we developed prediction models for detecting DN by logistic regression analyses, and the models were validated in 129 participants. Results: The blood level of D-serine above 2.34 uM demonstrated a high specificity of 83.3% (95% CI, 69.8-92.5%) for excluding participants without kidney diseases. In participants with the blood level of D-serine above 2.34 uM, the threshold of 46.6% in FE of D-serine provided an optimal threshold for the detection of DN [AUC, 0.85 (0.76-0.95); sensitivity, 78.8% (61.1-91.0%); specificity, 83.3% (CI, 67.2-93.6%). This plasma-high and FE-high profile of D-serine in combination with clinical factors (age, sex, estimated glomerular filtration rate, and albuminuria) correctly predicted DN with a sensitivity of 91.3% (95% confidence interval, 72.0-98.9%) and a specificity of 79.3% (63.3-80.0%), and outperformed the model based on clinical factors alone in the validation dataset (p < 0.015). Conclusions: Analysis of D-serine in blood and urinary excretion is useful in identifying DN in patients undergoing kidney biopsy. Profiling of D-serine in patients with kidney diseases supports the suitable treatment for the origins of kidney diseases.