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This study aimed to determine whether caffeine gum influenced perceptual-cognitive and physical performance during the extra-time period of simulated soccer match-play. Semiprofessional male soccer players (n = 12, age: 22 ± 3 years, stature: 1.78 ± 0.06 m, mass: 75 ± 9 kg) performed 120-min soccer-specific exercise on two occasions. In a triple-blind, randomized, crossover design, players chewed caffeinated (200 mg; caffeine) or control (0 mg; placebo) gum for 5 min following 90 min of soccer-specific exercise. Perceptual-cognitive skills (i.e., passing accuracy, reaction time, composure, and adaptability) were assessed using a soccer-specific virtual reality simulator, collected pre- and posttrial. Neuromuscular performance (reactive-strength index, vertical jump height, absolute and relative peak power output, and negative vertical displacement) and sprint performance (15 and 30 m) were measured at pretrial, half-time, 90 min, and posttrial. Caffeine gum attenuated declines in reaction time (pre: 90.8 ± 0.8 AU to post: 90.7 ± 0.8 AU) by a further 4.2% than placebo (pre: 92.1 ± 0.8 AU to post: 88.2 ± 0.8 AU; p <.01). Caffeine gum reduced composure by 4.7% (pre: 69.1 ± 0.8 AU to post: 65.9 ± 0.8 AU) versus placebo (pre: 68.8 ± 0.8 AU to post: 68.3 ± 0.8 AU; p <.01). Caffeine gum did not influence any other variables (p >.05). Where caffeine gum is consumed by players prior to extra-time, reaction time increases but composure may be compromised, and neuromuscular and sprint performance remain unchanged. Future work should assess caffeine gum mixes with substances like L-theanine that promote a relaxed state under stressful conditions. [ABSTRACT FROM AUTHOR]

Little is known about the motivations and outcomes of sellers in remunerated markets for human materials. We exploit dramatic growth in the U.S. blood plasma industry to shed light on the sellers of plasma. Sellers tend to be young and liquidity-constrained with low incomes and limited access to traditional credit. Plasma centers absorb demand for nontraditional credit. After a plasma center opens nearby, demand for payday loans falls by over 13% among young borrowers. Meanwhile, foot traffic increases by over 4% at nearby stores, suggesting that constrained households use plasma markets to smooth consumption without appealing to high-cost debt. [ABSTRACT FROM AUTHOR]

Background: Coronavirus-19 disease (COVID-19) frequently causes coagulation disturbances. Data remains limited on the effects of microRNAs (miRNAs) on coagulation during COVID-19 infection. We aimed to analyze the comprehensive miRNA profile as well as coagulation markers and blood count in hospitalized COVID-19 patients. Methods: Citrated plasma samples from 40 patients (24 men and 16 women) hospitalized for COVID-19 were analyzed. Basic coagulation tests, von Willebrand factor (VWF), ADAMTS13, blood count, C-reactive protein, and 27 miRNAs known to associate with thrombosis or platelet activation were analyzed. MiRNAs were analyzed using quantitative reverse transcription polymerase chain reaction (RT qPCR), with 10 healthy controls serving as a comparator. Results: Among the patients, 15/36 (41%) had platelet count of over 360 × 109/L and 10/36 (28%) had low hemoglobin of < 100 g/L, while 26/37 (72%) had high VWF of over 200 IU/dL. Patients had higher levels of the miRNAs miR-27b-3p, miR-320a-3p, miR-320b-3p, and miR-424-5p, whereas levels of miR-103a-3p and miR-145-5p were lower than those in healthy controls. In total, 11 miRNAs were associated with platelet count. Let-7b-3p was associated with low hemoglobin levels of < 100 g/L. miR-24-3p, miR-27b-3p, miR-126-3p, miR-145-5p and miR-338-5p associated with high VWF. Conclusion: COVID-19 patients differentially express miRNAs with target genes involved in fibrinolysis inhibition, coagulation activity, and increased inflammatory response. These findings support the notion that COVID-19 widely affects hemostasis, including platelets, coagulation and fibrinolysis. [ABSTRACT FROM AUTHOR]

Background: β-thalassemia (β-TH) is a hereditary hemolytic anemia that results in deficient hemoglobin (Hb) synthesis. It is characterized by ineffective erythropoiesis, anemia, splenomegaly, and systemic iron overload. Exploration new potential biomarkers and drug candidates is important to facilitate the prevention and treatment of β-TH. Methods: We applied quasi-targeted metabolomics between wild type (Wt) and heterozygous β-TH mice (Th3/+), a model of non-transfusion-dependent β-TH intermedia, in plasma and peripheral blood (PB) cells. Futher data was deeply mined by Kyoto Encyclopedia of Genomes (KEGG) and machine algorithms methods. Results: Using KEGG enrichment analysis, we found that taurine and hypotaurine metabolism disorders in plasma and alanine, aspartate and glutamate metabolism disorders in PB cells. After systematically anatomize the metabolites by machine algorithms, we confirmed that alpha-muricholic acidUP and N-acetyl-DL-phenylalanineUP in plasma and Dl-3-hydroxynorvalineUP, O-acetyl-L-serineUP, H-abu-OHUP, S-(Methyl) glutathioneUP, sepiapterinDOWN, and imidazoleacetic acidDOWN in PB cells play key roles in predicting the occurrence of β-TH. Furthermore, Sepiapterin, Imidazoleacetic acid, Methyl alpha-Dglucopyranoside and alpha-ketoglutaric acid have a good binding capacity to hemoglobin E through molecular docking and are considered to be potential drug candidates for β-TH. Conclusion: Those results may help in identify useful molecular targets in the diagnosis and treatment of β-TH and lays a strong foundation for further research. [ABSTRACT FROM AUTHOR]

Background: Beneficial effects from practising a Paleolithic diet as compared to a diabetes diet on weight, waist circumference, satiety, leptin, HbA1c and glucose control in randomised controlled trial participants with type 2 diabetes could be due to lower leptin resistance. Support for this hypothesis comes from an in vitro experiment that showed that digested wheat gluten, which is excluded from a Paleolithic diet, inhibits leptin from binding to its receptor, thus indicating a possible dietary cause of leptin resistance. However, the clinical relevance of the latter finding is unclear since removal of enzyme activity from the gluten digest by heat treatment also abolished leptin binding inhibition. Assessment of leptin binding inhibition in vivo is possible by comparison of total leptin levels with those of 'biologically active' leptin bound to its receptor (bioLep). Objectives: To assess the effects of a Paleolithic diet compared to a diabetes diet on leptin binding inhibition and to replicate our in vitro study. Methods: BioLep and total leptin levels were measured in secondary analysis of fasting plasma samples from our open label random order three plus three-month long cross-over trial performed in 2005–2007, that compared a Paleolithic diet with a diabetes diet in participants with type 2 diabetes without insulin treatment (per protocol). BioLep was also measured in vitro for known recombinant leptin concentrations incubated with a series of concentrations of 10 kDa spin-filtered digested wheat gluten, with or without prior heat treatment, at 100ºC for 30 min and centrifugation. Results: There was no difference between diets when comparing differences between bioLep and total leptin levels and their ratio in the 13 participants, three women and 10 men, aged 52–74 years with a mean BMI of 30 kg/m2 and a mean diabetes duration of eight years. We found no carry-over or period effect for bioLep and total leptin. In vitro, wheat gluten digest inhibited leptin binding in a dose-dependent manner but not after heat treatment. Conclusions: We found no leptin binding inhibition after the Paleolithic or diabetes diet, possibly due to its abolishment from cooking-related heat treatment of wheat gluten. Trial registration: Registered on 14/02/2007 at ClinicalTrials.gov Identifier: NCT00435240. [ABSTRACT FROM AUTHOR]

Background: Sonic Hedgehog (Shh), extensively researched for its role in early neurogenesis and brain development, has recently been recognized for its neuroprotective potential following neuronal injuries. This study examines the immediate impact of early administered Shh on the local inflammatory response post-acute spinal cord injury in rats. Methods: Thirty-four female Wistar rats underwent either sham surgery (laminectomy; n = 10) or clip compression/contusion spinal cord injury (SCI) at the T9 level. This was followed by implantation of an osmotic pump and a subdural catheter for continuous intrathecal delivery of Shh (n = 12) or placebo (NaCl; n = 12). Locomotor function was assessed at 3- and 7-days post-injury (dpi) using the Basso, Beattie, and Bresnahan (BBB) score and the Gridwalk test. Animals were euthanized after 3 or 7 days for immunohistochemical analysis of the local inflammatory reaction and immune cell migration. Results: Shh-treated rats demonstrated significant hindlimb movement and coordination improvements at 7 days post-injury, compared to controls. This enhancement was accompanied by a significant reduction in both immune cell presence and blood plasma products within spinal cord lesions, suggesting Shh's dual role in modulating immune cell migration and maintaining the integrity of the blood-spinal cord barrier. Separately, these Shh-treated rats also showed an increase in M(IL-4) polarization of macrophages, further underlining the potential therapeutic impact of Shh in post-injury recovery. Notably, these effects were not evident at three days post-injury. Conclusion: Shh application at 7 days post-injury showed immunomodulatory effects, possibly via enhanced blood-spinal cord barrier integrity, reduced immune cell migration, and increased anti-inflammatory immune cell differentiation. These mechanisms collectively contribute to enhanced locomotor recovery. [ABSTRACT FROM AUTHOR]

Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes. CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody. CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the Mmalton variant, and of Mprocida, I, Plowell and Mherleen in heterozygosity with Z-AAT. These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants. [ABSTRACT FROM AUTHOR]

Dysregulation of the CXCL12/CXCR4 axis is implicated in autoimmune, inflammatory, and oncogenic diseases, positioning CXCR4 as a pivotal therapeutic target. We evaluated optimized variants of the specific endogenous CXCR4 antagonist, EPI-X4, addressing existing challenges in stability and potency. Our structure-activity relationship study investigates the conjugation of EPI-X4 derivatives with long-chain fatty acids, enhancing serum albumin interaction and receptor affinity. Molecular dynamic simulations revealed that the lipid moieties stabilize the peptide-receptor interaction through hydrophobic contacts at the receptor's N-terminus, anchoring the lipopeptide within the CXCR4 binding pocket and maintaining essential receptor interactions. Accordingly, lipidation resulted in increased receptor affinities and antagonistic activities. Additionally, by interacting with human serum albumin lipidated EPI-X4 derivatives displayed sustained stability in human plasma and extended circulation times in vivo. Selected candidates showed significant therapeutic potential in human retinoblastoma cells in vitro and in ovo , with our lead derivative exhibiting higher efficacies compared to its non-lipidated counterpart. This study not only elucidates the optimization trajectory for EPI-X4 derivatives but also underscores the intricate interplay between stability and efficacy, crucial for delineating their translational potential in clinical applications. [Display omitted] • Lipidated derivatives of EPI-X4 exhibit increased affinity and antagonistic activity towards the CXCR4 receptor. • Lipidated EPI-X4 derivatives exhibit a half-life of >8 h in both blood and plasma. • The lipidated EPI-X4 JM#198 displays a circulation half-life of nearly 4 h in mice. • EPI-X4 JM#198 inhibits retinoblastoma tumor formation in vitro and in ovo. [ABSTRACT FROM AUTHOR]

Objectives Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by IL-1β. This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy. Methods Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1β levels during a FOP flare, further supporting a role of IL-1β in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient and describe 3 additional patients, from two medical centres. Results All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced a resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1β levels comparable to those in IL-1β-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales. Conclusion This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing the formation of new HO. Funding RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III. [ABSTRACT FROM AUTHOR]

Vasopressin or arginine‐vasopressin (AVP) is a neuropeptide molecule known for its antidiuretic effects and serves to regulate plasma osmolality and blood pressure. The existing literature suggests that AVP plays a multifaceted—though less well‐known—role in the central nervous system (CNS), particularly in relation to the pathophysiology and treatment of mood disorders. Animal models have demonstrated that AVP is implicated in regulating social cognition, affiliative and prosocial behaviors, and aggression, often in conjunction with oxytocin. In humans, AVP is implicated in mood disorders through its effects on the hypothalamic–pituitary–adrenal (HPA) axis as well as on the serotoninergic and glutamatergic systems. Measuring plasma AVP has yielded interesting but mixed results in mood and stress‐related disorders. Recent advances have led to the development of copeptin as a stable and reliable surrogate biomarker for AVP. Another interesting but relatively unexplored issue is the interaction between the osmoregulatory system and mood disorder pathophysiology, given that psychotropic medications often cause dysregulation of AVP receptor expression or signaling that can subsequently lead to clinical syndromes like syndrome of inappropriate diuresis and diabetes insipidus. Finally, pharmaceutical trials of agents that act on V1a and V1b receptor antagonists are still underway. This narrative review summarizes: (1) the neurobiology of the vasopressinergic system in the CNS; (2) the interaction between AVP and the monoaminergic and glutamatergic pathways in the pathophysiology and treatment of mood disorders; (3) the iatrogenic AVP dysregulation caused by psychotropic medications; and (4) the pharmaceutical development of AVP receptor antagonists for the treatment of mood disorders. [ABSTRACT FROM AUTHOR]

Purpose: Routine therapeutic drug monitoring of apixaban is currently not recommended but may however be warranted in some situations and for some patient groups to provide better and safer treatment. Due to limited data on apixaban concentrations in different subpopulations, it is still unclear which group of patients could possibly gain from monitoring. The purpose of this study was to examine apixaban exposure in patients with obesity compared with normal-weight patients. Methods: Forty patients with obesity (mean BMI 39.4 kg/m2) and 40 controls with normal weight (mean BMI 23.4 kg/m2), treated with apixaban 5 mg twice daily were included. The patients were matched for age, sex, and renal function. Trough and peak apixaban concentrations were measured with LC‒MS/MS methodology. Results: The median trough concentrations in patients with obesity (58.7, range 10.7–200.7 ng/ml) were slightly higher than those in patients with normal weight (52.0, range 31.0–150.9 ng/ml) (p < 0.05). Notably, the variability in trough concentration was considerably higher in patients with obesity. Peak concentrations were similar in both groups, with a median of 124.5 ng/ml (range 82.0–277.5) and 113.5 ng/ml (range 75.5–334.6) in patients with obesity and normal weight, respectively. Conclusion: Apixaban exposure did not vary substantially between obese and normal weight matched controls, implying that general dose adjustments are not required. However, vast interindividual variability was observed in patients with obesity, suggesting that measuring the concentrations could be valuable for specific patients. Further research is needed to identify which specific patients may benefit from this approach. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to examine the shear bond strength (SBS) of repair material to conventionally, subtractive‐, and additive‐manufactured denture bases after different surface treatments. Materials and Methods: Disk‐shaped test specimens (N = 300) were prepared from denture base materials produced by one conventional (Procryla), one subtractive (Yamahachi), and one additive (Curo Denture) method. The test specimens were randomly divided into five groups (n = 10) and exposed to a variety of surface treatments—Group A: no surface treatment; Group B: grinding with silicon carbide paper; Group C: sandblasting; Group D: erbium: yttrium‐aluminum‐garnet laser; and Group E: plasma. Repair was performed with autopolymerizing acrylic resin (Meliodent). Surface roughness analyses were performed with a profilometer. Scanning electron microscopy was used to examine one specimen from each subgroup. SBS was evaluated on a universal testing machine. Failure types were observed under a stereomicroscope. Results: Surface roughness values were significantly higher in all test materials in Group D than in the other groups (p < 0.001). For conventional resin, the SBS values were higher in Group C than in Groups A, D, and E (p < 0.001). For CAD/CAM material, Groups B and C had significantly greater SBS increases compared with Group E (p < 0.001). For 3D material, Group D showed higher SBS than all groups except Group C (p < 0.001). Conclusions: For SBS, sandblasting was most effective in the conventional group, whereas laser treatment was the most effective in the additive‐manufactured group. For the subtractive group, surface treatments other than plasma exhibited similar SBS. Clinical Significance: In repairing fractured prostheses, any degree of roughening suitable for the material content may provide an SBS benefit. [ABSTRACT FROM AUTHOR]

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight‐based loading doses of LEV with respect to established therapeutic target concentrations. Meta‐regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight‐based dosing) to achieve maximum (Cpeak) and 12‐h (C12h) plasma concentrations that exceed 12 mg/L. The meta‐regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight‐based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight‐based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing. [ABSTRACT FROM AUTHOR]

Context Although the nutritional composition of organic food has been thoroughly researched, there is a dearth of published data relating to its impact on human health. Objective This systematic review aimed to examine the association between organic food intake and health effects, including changes in in vivo biomarkers, disease prevalence, and functional changes. Data Sources PubMed, EMBASE, Web of Science, the Cochrane Library, and ClinicalTrials.gov were searched from inception through Nov 13, 2022. Data Extraction Both observational and interventional studies conducted in human populations were included, and association between level of organic food intake and each outcome was quantified as "no association," "inconsistent," "beneficial correlation/harmful correlation," or "insufficient". For outcomes with sufficient data reported by at least 3 studies, meta-analyses were conducted, using random-effects models to calculate standardized mean differences. Data Analysis Based on the included 23 observational and 27 interventional studies, the association between levels of organic food intake and (i) pesticide exposure biomarker was assessed as "beneficial correlation," (ii) toxic metals and carotenoids in the plasma was assessed as "no association," (iii) fatty acids in human milk was assessed as "insufficient," (iv) phenolics was assessed as "beneficial", and serum parameters and antioxidant status was assessed as "inconsistent". For diseases and functional changes, there was an overall "beneficial" association with organic food intake, and there were similar findings for obesity and body mass index. However, evidence for association of organic food intake with other single diseases was assessed as "insufficient" due to the limited number and extent of studies. Conclusion Organic food intake was found to have a beneficial impact in terms of reducing pesticide exposure, and the general effect on disease and functional changes (body mass index, male sperm quality) was appreciable. More long-term studies are required, especially for single diseases. Systematic Review Registration PROSPERO registration no. CRD42022350175. [ABSTRACT FROM AUTHOR]

Context: Preeclampsia is a common pregnancy complication, posing significant risks to both the mother and fetus. Predicting and determining the risks of this disease is crucial. Aims: This research aims to understand the pathogenetic role of several factors in the development and progression of preeclampsia, particularly in relation to its severity in pregnant patients. Methods: The study included 60 pregnant women diagnosed with either mild or severe preeclampsia and 40 healthy pregnant women for comparison. Blood plasma was analysed using biochemical methods, and blood microcirculation parameters were determined to identify homeostatic abnormalities in early preeclampsia. Key results: A molecular genetic study revealed the frequency of the endothelial nitric oxide gene eNOSC774T. Homeostatic abnormalities were statistically correlated with polymorphic genotypes of the eNOSC774T gene. Conclusions: The research found a correlation between the T774T eNOS genotype mutation and the severity of preeclampsia, alongside significant homeostasis abnormalities in patients. Implications: The T774T mutant genotype of the eNOS gene and higher levels of lipid peroxidation products are strongly linked to the severity and progression of preeclampsia. This highlights a significant connection between genetic predisposition and biochemical abnormalities in the disease's development. Preeclampsia is one of the common complications of pregnancy, posing a significant risk to the life and health of the pregnant woman and fetus, which is why it is so important to achieve predictability and determine the risks of the disease. This research aims to determine the pathogenetic role of several factors in the development of preeclampsia and its progression in association with the severity of pregnant patients. Sixty pregnant women diagnosed with preeclampsia, both mild and severe, were enrolled. Forty healthy pregnant women were also studied for comparison. Image by Irina Ismailova. [ABSTRACT FROM AUTHOR]

Introduction and Objectives: Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide. A considerable proportion of HCC is caused by cirrhosis related to metabolic dysfunction-associated steatohepatitis (MASH). Due to the increasing prevalence of metabolic syndrome, it is estimated that MASH-related HCC will become the most prevalent etiology of HCC. Currently, HCC screening is based on liver ultrasonography; however, the sensitivity of ultrasonography for early HCC stages in obese patients only reaches 23 %. To date, no studied biomarker shows sufficient efficacy for screening purposes. Nevertheless, the usage of spectroscopic methods offers a new perspective, as its potential use would provide cheap, fast analysis of samples such as blood plasma. Material and Methods: We employed a combination of conventional and chiroptical spectroscopic methods to study differences between the blood plasma of obese cirrhotic patients with and without HCC. We included 20 subjects with HCC and 17 without evidence of liver cancer, all of them with body mass index ≥ 30. Results: Sensitivities and specificities reached values as follows: 0.780 and 0.905 for infrared spectroscopy, 0.700 and 0.767 for Raman spectroscopy, 0.840 and 0.743 for electronic circular dichroism, and 0.805 and 0.923 for Raman optical activity. The final combined classification model based on all spectroscopic methods reached a sensitivity of 0.810 and a specificity of 0.857, with the highest area under the receiver operating characteristic curve among all models (0.961). Conclusions: We suggest that this approach can be used effectively as a diagnostic tool in patients who are not examinable by liver ultrasonography. [ABSTRACT FROM AUTHOR]

Background Carriers of germline pathogenic variants (PVs) in succinate dehydrogenase genes (SDHx) are at risk of developing tumors, including paragangliomas, gastrointestinal stromal tumors, and renal cell carcinomas. Early tumor detection is paramount for improved clinical outcome. Blood-based biomarkers could aid in identifying individuals with PVs early and provide functional evidence in patients with variants of unknown significance. Methods Blood plasma, urine, peripheral blood mononuclear cells, and erythrocytes from patients with and without SDHx PVs were investigated for central carbon metabolites. These were measured by liquid chromatography–tandem mass spectrometry and nuclear magnetic resonance spectroscopy and included among others, succinate, fumarate, α-ketoglutarate, and lactate. Results Plasma succinate to fumarate ratios effectively distinguished tumor-bearing and asymptomatic patients with and without SDHx PV with promising diagnostic performance (areas under the receiver operating characteristic curve 0.86-0.95), although higher levels were noted in individuals with SDHB PV. Metabolites in urine and in peripheral blood mononuclear cell extracts were largely similar between groups. Erythrocytes showed strong metabolic alterations in patients with SDHx PV compared to controls, with 8 of 13 low-molecular organic acids being significantly different (P <.05). The lactate-α-ketoglutarate-ratio of erythrocytes identified individuals with SDHx PV equally well as plasma, with a sensitivity and specificity of 92% (AUC 0.97). Conclusion Blood biomarkers have been underutilized for identifying carriers of SDHx PV or to validate variants of unknown significance. Our findings advocate for further investigation into a combined approach involving plasma and erythrocytes for future diagnostic strategies. [ABSTRACT FROM AUTHOR]

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Electroless NiP coatings are well known for their excellent properties and vast area of applications. In the present investigation, electroless NiP coating is applied on AISI 420 substrate, which is used for manufacturing medical instruments. As blood is a strong electrolyte, the steel, when comes in contact with blood for a long time, tends to corrode very fast. The primary objective of this work is to enhance the corrosion resistivity of AISI 420 stainless steel by the application of electroless NiP coating. The corrosion resistance of coated steel was investigated using both potentiodynamic polarisation and electrochemical impedance spectroscopy in artificial blood plasma. Detailed microstructural investigation using scanning electron microscopy (SEM), X-ray diffraction and energy dispersive X-ray spectroscopy has been done. Microhardness measurement has been performed. The SEM images revealed the coatings to be primarily amorphous and changed to crystalline when heat treated at 300°C for 2 h. Microhardness of the as-plated coating was 592 HV and increased to 677 HV after heat treatment. Corrosion rate decreased from 4.694 × 10−4 mm/year of bare steel to 4.104 × 10−5 mm/year for coated and heat-treated steel. [ABSTRACT FROM AUTHOR]

Background/Objectives: Reduced serum magnesium (Mg) levels have been associated with obesity, insulin resistance (IR), type 2 diabetes, and metabolic syndrome in adults. However, in the children population, the evidence is still limited. In this cross-sectional study, we aimed to analyze the association of serum Mg levels with the frequency of overweight and obesity and cardiometabolic traits in 189 schoolchildren (91 girls and 98 boys) between 6 and 12 years old from Mexico City. Subjects/Methods: Anthropometrical data were collected and biochemical parameters were measured by enzymatic colorimetric assay. Serum Mg level was analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The triglyceride-glucose (TyG) index was used as a surrogate marker to evaluate IR. Results: Serum Mg level was negatively associated with overweight (Odds ratio [OR] = 0.377, 95% confidence interval [CI] 0.231–0.614, p < 0.001) and obesity (OR = 0.345, 95% CI 0.202–0.589, p < 0.001). Serum Mg level resulted negatively associated with body mass index (BMI, β = −1.16 ± 0.26, p < 0.001), BMI z-score (β = −0.48 ± 0.10, p < 0.001) and TyG index (β = −0.04 ± 0.04, p = 0.041). Through a mediation analysis was estimated that BMI z-score accounts for 60.5% of the negative association of serum Mg level with IR (Sobel test: z = 2.761; p = 0.005). Conclusion: Our results evidence that BMI z-score mediate part of the negative association of serum Mg level and IR in Mexican schoolchildren. [ABSTRACT FROM AUTHOR]

To overcome the poor targeting of conventional chemotherapeutic drugs and the defects of low drug‐loading capacity of conventional drug delivery systems, novel drug delivery systems with high drug‐loading capacity are developed. Herein, the high drug‐loaded mPEG79‐GFLGDDD‐DOX copolymer is first synthesized via an amide reaction, which can bond multiplex DOX. After PEGylation, the drug can resist the adsorption of proteins in the plasma in blood circulation, avoid being rapidly cleared out of the body, and prolong the circulation time of the drug in the blood, which is conducive to the enrichment of micelles in tumor tissues through the EPR effect. In tumor tissues, the peptide Glycine‐ Phenylalanine‐ Leucine‐ Glycine (GFLG) is recognized and sheared by overexpressed cathepsin B, which stripped the outer layer of methoxy polyethylene glycol (mPEG) and made it more readily available for uptake by tumor cells. After entering the tumor cells, the bonded DOX and the physically encapsulated DOX in the micelles played a synergistic role, realizing the killing of tumor cells, thus effectively enhancing the therapeutic effect on tumors. The findings in this work suggest that a high drug‐loading drug delivery system has great potential in the clinical treatment of tumors. [ABSTRACT FROM AUTHOR]

Background: The previously underestimated effects of commensal gut microbiota on the human body are increasingly being investigated using omics. The discovery of active molecules of interaction between the microbiota and the host may be an important step towards elucidating the mechanisms of symbiosis. Results: Here, we show that in the bloodstream of healthy people, there are over 900 peptides that are fragments of proteins from microorganisms which naturally inhabit human biotopes, including the intestinal microbiota. Absolute quantitation by multiple reaction monitoring has confirmed the presence of bacterial peptides in the blood plasma and serum in the range of approximately 0.1 nM to 1 μM. The abundance of microbiota peptides reaches its maximum about 5 h after a meal. Most of the peptides correlate with the bacterial composition of the small intestine and are likely obtained by hydrolysis of membrane proteins with trypsin, chymotrypsin and pepsin – the main proteases of the gastrointestinal tract. The peptides have physicochemical properties that likely allow them to selectively pass the intestinal mucosal barrier and resist fibrinolysis. Conclusions: The proposed approach to the identification of microbiota peptides in the blood, after additional validation, may be useful for determining the microbiota composition of hard-to-reach intestinal areas and monitoring the permeability of the intestinal mucosal barrier. [ABSTRACT FROM AUTHOR]

Background and Objectives Materials and Methods Results Conclusion Facemasks represent an essential measure of prevention against the spread of infectious diseases; however, they lessen the ability to convey and understand emotions through facial expressions. In blood donation settings, facemask wearing could interfere with professionals' tasks, reduce the satisfaction of blood donors and affect their future blood donation behaviour. This preliminary cross‐sectional study explored the association of mandatory facemask wearing with the quality of the blood donation process at the end of the coronavirus 2019 (COVID‐19) pandemic.A sample of 615 voluntary unpaid Italian blood and plasma donors completed an online survey assessing their attitude towards facemask wearing, the perceived distress due to facemasks in the different steps of the donation process, self‐reported vasovagal reactions after donation and the intention to donate again.Nearly 24% of donors reported a worsened quality of the donation process due to facemask wearing, and 36% reported moderate to severe distress during the donation itself. Donors with a more negative attitude towards facemasks reported a worse donation experience, mainly related to the interactions and the communication with physicians and nurses, and a higher probability of experiencing vasovagal reactions at their last donation. No significant correlations were observed between negative facemask attitudes towards facemask wearing, distress or future intention to donate blood/plasma.Facemasks have worsened the quality of blood and plasma donations for one fourth of donors, confirming the interference with the quality of communications and relationships with healthcare professionals. [ABSTRACT FROM AUTHOR]

Most albumin in blood plasma is thought to be monomeric with some 5% covalently dimerized. However, many reports in the recent biophysics literature find that albumin is reversibly dimerized or even oligomerized. We review data on this from X‐ray crystallography and diverse biophysical techniques. The number‐average molecular weight of albumin would be increased by dimerization, affecting size‐dependent filtration processes of albumin such as at the glycocalyx of the capillary endothelium and the podocyte slit‐diaphragm of the renal glomerulus. If correct, and depending on characteristics of the process, such as Kd, reversible dimerization of albumin in plasma would have major implications for normal physiology and medicine. We present quantitative models of the impact of dimerization on albumin molecular forms, on the number‐average molecular weight of albumin, and estimate the effect on the colloid osmotic pressure of albumin. Dimerization reduces colloid osmotic pressure as total albumin concentration increases below that expected in the absence of dimerization. Current models of albumin filtration by the renal glomerulus would need revision to account for the dynamic size of albumin molecules filtered. More robust biophysical data are needed to give a definitive answer to the questions posed and we suggest possible approaches to this. [ABSTRACT FROM AUTHOR]

An imbalance in cysteine (Cys) levels in the cells and plasma has been identified as the risk indicator for various human diseases. The structural similarity of cysteine with its congener homocysteine and glutathione offers challenges in its measurement. Herein, we report a hydrogen‐bonded organic‐inorganic framework of Cu(II) (HOIF) for the selective detection of cysteine over other biothiols. The non‐fluorescent HOIF showed 12‐fold green emission in the presence of cysteine. The monomeric unit of HOIF is stabilized via intermolecular hydrogen bonds, resulting in a non‐porous network structure. Non‐interference from homocysteine, glutathione, and other competitive bio‐analytes revealed explicit affinity of HOIF for cysteine. Fluorimetric titration showed a wide working concentration window (650 nM–800 μM) for measuring cysteine in an aqueous medium. The mechanistic investigation involving HRMS, EPR, and UV‐vis spectroscopic studies revealed the decomplexation of HOIF with Cys, resulting in a fluorescence turn‐on response from the luminescent ligand. Validation using a commercial dye, “Cysteine Green”, confirmed the prospect of HOIF for early diagnostic purposes. Utilizing the fluorescence turn‐on property of HOIF in the presence of cysteine, we measured cysteine quantitatively in the blood plasma samples. Bio‐imaging of endogenous cysteine in cancer cells indicated the ability of HOIF to monitor the intracellular cysteine. [ABSTRACT FROM AUTHOR]

High‐starch diets may affect equine hindgut microbiota and increase blood glucose levels, which may cause unwanted physiological changes, but may also elicit behavioural changes such as increased fear reactions. The purpose of the current study was to feed a high starch (300) and low fat (43; HS_LF) or a low starch (60) and high fat (85; LS_HF, g/kg of DM) concentrate within the available commercial range and investigate how muscle endurance and fear reactions of horses respond to different diets. Twenty Danish Warmblood stallions (4 years) were randomly allocated to two treatments: LS_HF (n = 10) and HS_LF (n = 10) for 9 weeks. During the two last weeks, a single step exercise test was performed, and plasma metabolites and blood gases were measured before and after exercise in a 2 × 2 factorial design. The effect of two diets on fearfulness was tested by exposing the horses to novel objects test (T1 and T2). Plasma metabolites was not affected by diets. However, plasma level of glucose post‐exercise (4.9) was lower than pre‐exercise (5.6 mmol/L; p < 0.001). Similarly, plasma level of insulin post‐exercise (4.2) was lower than pre‐exercise (13.1 pmol/L; p < 0.001). Plasma level of lactate dehydrogenase (p < 0.001), non‐esterified fatty acids (p = 0.002), β‐hydroxybutyrate (p = 0.001), and fructosamine (p = 0.01) post‐exercise was higher than pre‐exercise. Regardless of type of diets, RRR‐α‐tocopherol was the dominance α‐tocopherol stereoisomers in plasma. In conclusion, during aerobic exercise, fat to starch ratio in horse diets within the normal range had no significant effect on plasma metabolites. However, horses fed LS_HF tended to show more investigative behaviour than horses fed HS_LF. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized classical treatment approaches of various cancer entities, but are also associated with a number of side effects. One of these may be life-threatening clotting disorders with the risk of thrombotic or hemorrhagic complications, the mechanisms of which are still poorly understood. In the present study, we analyzed the direct effects of pembrolizumab, nivolumab, and ipilimumab on platelet aggregation as well as plasma coagulation followed by fibrinolysis in an ex vivo model. Methods: Microplate spectrometry was used to analyze aggregation, coagulation, and fibrinolysis in platelet-free (PFP) and platelet-rich (PRP) healthy donor plasma samples treated with pembrolizumab, nivolumab, ipilimumab, and appropriate isotype controls. Aggregation was induced by TRAP-6. Clotting of PFP and PRP followed by lysis was initiated with a tissue factor in a mixture of phosphatidylserine:phosphatidylcholine and the addition of t-PA. Among other parameters, the area under the curve (AUC) was used to compare the effect of ICIs on aggregation, coagulation, and fibrinolysis. Results: Upon direct contact with platelets, pembrolizumab stimulated platelet aggregation in PRP, while nivolumab and ipilimumab promoted disaggregation with corresponding changes in the AUC. Pembrolizumab and nivolumab, both PD-1 receptor inhibitors, had no effect on the plasma coagulation cascade. Ipilimumab, a CTLA-4 receptor inhibitor, significantly increased the rate of PRP clotting. When clotting was followed by lysis, all ICIs were found to prolong the growth of the PRP-derived fibrin clot and delay its elimination. This was manifested by an increase in AUC relative to control PRP. Conclusion: This study characterizes the potential impact of pembrolizumab, nivolumab, and ipilimumab on hemostasis. Nivolumab and ipilimumab are able to reduce aggregation and increase the procoagulant properties of platelets, which can cause side effects associated with hemostatic imbalance leading to thrombosis or bleeding. The observed ICI-specific effects may contribute to our understanding of the mechanisms by which ICI affects platelets and suggest how, in a clinical setting, to reduce coagulation disorders during ICI treatment in the future. [ABSTRACT FROM AUTHOR]

The hyphenation of HPLC with its high separation ability and ICP-MS with its excellent sensitivity, allows the analysis of Pt drugs in biological samples at the low nanomolar concentration levels. On the other hand, LC-MS provides molecular structural confirmation for each species. Using a combination of these methods, we have investigated the speciation of the photoactive anticancer complex diazido Pt(IV) complex trans, trans, trans-[Pt(N3)2(OH)2(py)2] (FM-190) in aqueous solution and biofluids at single-digit nanomolar concentrations before and after irradiation. FM-190 displays high stability in human blood plasma in the dark at 37 °C. Interestingly, the polyhydroxido species [{PtIV(py)2(OH)4} + Na]+ and [{PtIV(py)2(N3)(OH)3} + Na]+ resulting from the replacement of azido ligands, as determined by LC-MS, were the major products after photoirradiation of FM-190 with blue light (463 nm). This finding suggests that such photosubstituted Pt(IV) tri- and tetra-hydroxido species could play important roles in the biological activity of this anticancer complex. Density Functional Theory (DFT) and Time-Dependent DFT (TDDFT) calculations show that these Pt(IV) species arising from FM-190 in aqueous media can be formed directly from a singlet excited state. The results highlight how speciation analysis (metallomics) can shed light on photoactivation pathways for FM-190 and formation of potential excited-state pharmacophores. The ability to detect and identify photoproducts at physiologically-relevant concentrations in cells and tissues will be important for preclinical development studies of this class of photoactivatable platinum drugs. [ABSTRACT FROM AUTHOR]

Background: The presence of a polymicrobial dysbiotic film in direct and constant contact with periodontal tissues initiates the host immune response. Interleukin 18 (IL-18) triggers up-regulates the production of other proinflammatory cytokines (TNF-α, IL-1β, IL-6), creating a vicious cycle that expands the inflammatory and destructive process in the periodontal tissue. A systematic review and meta-analysis was carried out with the main propose to investigate IL-18 expression in different biological samples from subjects with chronic periodontitis. Methods: The protocol followed PRISMA guidelines and was registered in Open Science Framework (OSF):https://doi.org/10.17605/OSF.IO/BS9GM. A digital search was conducted in the databases PubMed, ScienceDirect, Google Scholar, Web of Science and Dentistry & Oral Sciences Source databases were consulted from March 15th, 2005 to February 10th, 2023. Study quality was assessed using the JBI tool for cross-sectional studies and clinical trials. A meta-analysis was performed using a random/fixed effects model to evaluate the concentration of IL-18 in serum, plasma, saliva, gingival tissue and GCF of exposure group compared to control group. Results: The search strategy provided a total of 3,156 articles, of which 18 investigations met the inclusion criteria and 15 articles were quantitatively analyzed. The total number of patients studied was 1,275 (682 cases and 593 controls). The meta-analysis revealed significantly elevated IL-18 levels of serum, saliva and GCF of subjects with chronic periodontitis compared to healthy subjects (Serum: SMD = 62.73, 95%CI: 25.43-100.03, Z = 3.29, p = 0.001*; Saliva: SMD = 243.63, 95%CI: 8.68-478.59, Z = 2.03, p = 0.042*; GCF: SMD = 150.26, 95%CI: 56.86-243.66, Z = 3.15, p = 0.02*). Conclusion: IL-18 levels in serum, saliva and GCF could have the potential to be used as complementary diagnostic tools to the clinical and radiographic parameters in subjects with periodontitis. [ABSTRACT FROM AUTHOR]

Simple Summary: The increasing use of automated milking systems (AMS) in the dairy industry has led to the necessity for changes in management practices implemented by producers. This study investigated the productive and metabolic impact of three versus six milkings per day (MPD) during early lactation on multiparous Holstein cows managed in an AMS. Mature cows (third and greater parity) with six MPD had greater milk fat production during the experimental phase (4 to 29 days in milk; DIM) and milk production during the carryover phase (30 to 90 DIM) than mature three MPD cows. The composition of milk fatty acids differed between MPD groups with cows, with three MPD having greater short-, medium-, odd- and branched-chain fatty acids during the experimental phase compared to cows with six MPD. Based on greater blood fatty acid and β-hydroxybutyrate concentrations, the mature six MPD cows may have been in a greater postpartum nutrient deficit and at greater risk of metabolic illness. Our findings suggest a need to strategically manage the MPD or nutrition of mature, early lactation dairy cows in an AMS. Automated milking systems (AMS) are increasingly adopted for dairy cow production, promoting individualized cow management dependent on factors like lactation stage, age, and productivity. The study objective was to investigate the effects of early lactation milking frequency on cows milked via AMS. Multiparous Holstein cows blocked by parity and due date were randomly assigned to treatments (n = 8 per treatment): three (3X) or six (6X) milkings per day (MPD). The experimental phase (EXP) was defined as 4 to 29 days in milk (DIM). The AMS settings were programed so 3X cows were limited to three MPD while 6X cows were allowed six MPD. Afterwards was the carry over phase (CO) ranging from 30 to 90 DIM; all cows were allowed up to six MPD. Measurements by the AMS included bodyweight, milk yield (MY), and pellet intake. Weekly composite milk samples were analyzed for macronutrient composition and fatty acid (FA) profile. Coccygeal blood was sampled at 3, 8 ± 1, and 13 ± 1 DIM; concentrations of blood plasma analytes were quantified. Greater MPD was achieved for 6X cows versus 3X cows during EXP, but similar during the CO. Daily MY was non-separable during the EXP while 6X cows in their third or greater lactation group (3 + LG) had greater MY than 3X cows of the same LG during the CO. Milk fat content and 4% fat-corrected MY were both greater for 6X, 3 + LG cows during the EXP compared to 3X, 3 + LG cows. Milk FA methyl esters (FAME) proportions were different between MPD groups, with 6X, 3 + LG cows having the lowest short, even-chain FA from de novo or post-absorptive origin. Differences in analytes indicated that 6X, 3 + LG cows experienced metabolic stress and incorporated greater FA from adipose tissue. Greater early lactation MPD in AMS may shift cow nutrient partitioning to support greater production in 3+ parity cows. [ABSTRACT FROM AUTHOR]

Background: Type 1 diabetes mellitus (T1DM) is well-known to trigger a disruption of lipid metabolism. This study aimed to compare lipid profile changes in T1DM patients after achieving glucose control and explore the underlying mechanisms. In addition, we seek to identify novel lipid biomarkers associated with T1DM under conditions of glycemic control. Methods: A total of 27 adults with T1DM (age: 34.3 ± 11.2 yrs) who had maintained glucose control for over a year, and 24 healthy controls (age: 35.1 + 5.56 yrs) were recruited. Clinical characteristics of all participants were analyzed and plasma samples were collected for untargeted lipidomic analysis using mass spectrometry. Results: We identified 594 lipid species from 13 major classes. Differential analysis of plasma lipid profiles revealed a general decline in lipid levels in T1DM patients with controlled glycemic levels, including a notable decrease in triglycerides (TAGs) and diglycerides (DAGs). Moreover, these T1DM patients exhibited lower levels of six phosphatidylcholines (PCs) and three phosphatidylethanolamines (PEs). Random forest analysis determined DAG(14:0/20:0) and PC(18:0/20:3) to be the most prominent plasma markers of T1DM under glycemic control (AUC = 0.966). Conclusions: The levels of all metabolites from the 13 lipid classes were changed in T1DM patients under glycemic control, with TAGs, DAGs, PCs, PEs, and FFAs demonstrating the most significant decrease. This research identified DAG(14:0/20:0) and PC(18:0/20:3) as effective plasma biomarkers in T1DM patients with controled glycemic levels. [ABSTRACT FROM AUTHOR]

Background: Identifying molecular mechanisms responsible for the response to heat stress is essential to increase production, reproduction, health, and welfare. This study aimed to identify early biological responses and potential biomarkers involved in the response to heat stress and animal's recovery in tropically adapted beef cattle through proteomic analysis of blood plasma. Methods: Blood samples were collected from 14 Caracu males during the heat stress peak (HSP) and 16 h after it (heat stress recovery--HSR) assessed based on wet bulb globe temperature index and rectal temperature. Proteome was investigated by liquid chromatography-tandem mass spectrometry from plasma samples, and the differentially regulated proteins were evaluated by functional enrichment analysis using DAVID tool. The protein-protein interaction network was evaluated by STRING tool. Results: A total of 1,550 proteins were detected in both time points, of which 84 and 65 were downregulated and upregulated during HSR, respectively. Among the differentially regulated proteins with the highest absolute log-fold change values, those encoded by the GABBR1, EPHA2, DUSP5, MUC2, DGCR8, MAP2K7, ADRA1A, CXADR, TOPBP1, and NEB genes were highlighted as potential biomarkers because of their roles in response to heat stress. The functional enrichment analysis revealed that 65 Gene Ontology terms and 34 pathways were significant (P < 0.05). We highlighted those that could be associated with the response to heat stress, such as those related to the immune system, complement system, hemostasis, calcium, ECM-receptor interaction, and PI3K-Akt and MAPK signaling pathways. In addition, the protein-protein interaction network analysis revealed several complement and coagulation proteins and acute-phase proteins as important nodes based on their centrality and edges. Conclusion: Identifying differentially regulated proteins and their relationship, as well as their roles in key pathways contribute to improve the knowledge of the mechanisms behind the response to heat stress in naturally adapted cattle breeds. In addition, proteins highlighted herein are potential biomarkers involved in the early response and recovery from heat stress in tropically adapted beef cattle. [ABSTRACT FROM AUTHOR]

This work presents an innovative platform of a multi-channel one-dimensional photonic crystal (1-DPC) based on blood refractive index data of different patients in the aspect of the main protein components like hemoglobin. This photonic crystal (PC) contains a defect center infiltrated with plasma using a microorder size syringe. When binary silica and III–V semiconductor (InSb) materials are combined, they increase the refractive index difference between the alternate layers of the composite material, resulting in a wide photonic band gap (PBG). We use the well-known transfer matrix method (TMM) to observe the reflectance of various blood samples that were previously published. We assess and contrast the influence of different refractive index data on the dynamic shift in PBG calculation for novel superior and resourceful sensor in the prevention of microscopic organisms such as SARS-CoV-2, the virus linked with COVID-19. Yet, the performance of this PC has more moral content and unlimited casting efficacy in the face of an incurable virus. [ABSTRACT FROM AUTHOR]

Haptoglobin is a plasma protein of mammals that plays a crucial role in vascular homeostasis by binding free haemoglobin released from ruptured red blood cells. Trypanosoma brucei can exploit this by internalising haptoglobinhaemoglobin complex to acquire host haem. Here, we investigated the impact of haptoglobin deficiency (Hp-/-) on T. brucei brucei infection and the parasite´s capacity to internalise haemoglobin in a Hp-/- mouse model. The infected Hp-/- mice exhibited normal disease progression, with minimal weight loss and no apparent organ pathology, similarly to control mice. While the proteomic profile of mouse sera significantly changed in response to T. b. brucei, no differences in the infection response markers of blood plasma between Hp-/- and control Black mice were observed. Similarly, very few quantitative differences were observed between the proteomes of parasites harvested from Hp-/- and Black mice, including both endogenous proteins and internalised host proteins. While haptoglobin was indeed absent from parasites isolated from Hp-/-mice, haemoglobin peptides were unexpectedly detected in parasites from both Hp-/- and Black mice. Combined, the data support the dispensability of haptoglobin for haemoglobin internalisation by T. b. brucei during infection in mice. Since the trypanosomes knock-outs for their haptoglobin-haemoglobin receptor (HpHbR) internalised significantly less haemoglobin from Hp-/- mice compared to those isolated from Black mice, it suggests that T. b. brucei employs also an HpHbR-independent haptoglobin-mediated mode for haemoglobin internalisation. Our study reveals a so-far hidden flexibility of haemoglobin acquisition by T. b. brucei and offers novel insights into alternative haemoglobin uptake pathways. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) patients are more prone to develop cardiovascular complications, and there is a dire need of a routine screening tool for risk assessment of heart failure (HF) in them. Aims and Objectives: The current study was conducted to estimate the levels of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in subjects with and without T2DM and evaluate the association between NT-proBNP and body mass index (BMI), waist circumference as markers of obesity, hemoglobin A1c (HbA1c), plasma fasting blood sugar (FBS), plasma postprandial blood sugar (PPBS),duration of diabetes as markers of glycemic control and serum C-reactive protein (CRP),an inflammatory marker in diabetic subjects. Materials and Methods: A hospital-based cross-sectional non-interventional study was done with 82 non-diabetic healthy volunteers and 82 T2DM patients. Anthropometric measurements (waist circumference [WC] and body mass index [BMI]) were recorded, and blood was analyzed for serum NT-proBNP, C-reactive protein (CRP), plasma fasting blood sugar (FBS), postprandial blood sugar (PPBS), and hemoglobin A1c (HBA1c). Data collected were analyzed by statistical software with P<0.05 as the significance level. Results: Serum NT-proBNP level was significantly higher in diabetic group (P<0.001) compared to non-diabetic group statistically. Correlation analysis in diabetic subjects showed a significant positive correlation of NT-proBNP with CRP (ρ+0.576, P<0.001), duration of diabetes (ρ+0.780, P<0.001), plasma FBS (ρ+0.524, P=0.003), plasma PPBS (ρ+0.673, P=0.013), and HbA1c (ρ+0.571, P=0.001) but there was no statistically significant correlation of NT-proBNP with BMI or WC values although the correlation was negative for both. Conclusion: The present study provides a novel perspective that measuring serum NT-proBNP may help in the earlier identification of impending HF in diabetic individuals assisting in prompt intervention which may be further confirmed by larger studies. [ABSTRACT FROM AUTHOR]

The effect of the lipid extract isolated from the tunic of the marine hydrobiont Halocynthia aurantium was studied. Its administration during hypothermia, hyperthermia, muscle load, introduction of hexenal, and the vertical fixation by the dorsal neck fold, as well as its embryotoxic and teratogenic effects, was evaluated. The impact of stress (vertical fixation of rats by the dorsal neck fold) was accompanied by an increase in the plasma levels of total lipids, total cholesterol, cholesterol/phospholipid ratios, and a decrease in the total phospholipids, as well as by a change in the quantitative characteristics of classes of neutral and phospholipids. A correction of the developed changes by a lipid extract of ascidia and a commercial reference preparation Omega-3 was carried out. The lipid extract of H. aurantium showed a higher efficiency in restoring the lipid composition of the blood plasma under stress impact compared to the preparation Omega-3 due to the wider range of neutral and phospholipid classes, polyunsaturated fatty acids of the n-3 and n-6 families. The tunic of ascidian can be used as a raw material for obtaining preparations with stress-protector and lipid-correcting properties. [ABSTRACT FROM AUTHOR]

Introduction: An investigation of the suitability of reagents for measuring FVIII products in a one‐stage clotting assay (OSA) showed variations in their FVIII activity (FVIII:C). Most studies have focused on the activated partial thromboplastin time (APTT) reagent rather than FVIII‐deficient plasma (F8DP), even though the APTT‐based OSA is comprised of APTT reagents and factor‐deficient plasma. Aim: A single‐centre study was conducted to clarify variations in measurements of FVIII products in an OSA using a total of 12 reagent combinations, including four APTT reagents and three types of F8DP. Methods: FVIII:C in nine types of FVIII product‐spiked plasma was measured using an OSA with four different APTT reagents and three types of F8DP. Results: F8DP‐dependent variations were found in addition to differences derived from APTT reagents. Variations in target recovery (TR) were observed for NovoEight®, Eloctate®, and Jivi®. Reduced TR for Jivi was found only for Pathromtin SL in combination with congenital F8DP (F8DP‐3). This lower TR was not observed with alternative manufacturing lots of F8DP‐3. The reduced TR for Jivi might be related to impaired contact activation due to lower factor XI activity in F8DP‐3. Conclusion: In addition to APTT reagents, variations in F8DPs used for OSAs can also affect FVIII:C results. F8DPs as well as the APTT reagent used for OSA should be chosen with caution, and laboratories should evaluate reagents for F8DPs as they currently do for APTT reagents, especially when lot changes occur. [ABSTRACT FROM AUTHOR]

BI 187004, a selective small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1), displayed complex nonlinear pharmacokinetics (PK) in humans. Following nine single oral doses, BI 187004 exhibited nonlinear PK at low doses and linear PK at higher doses. Notably, substantial hepatic 11β‐HSD1 inhibition (50%) was detected in a very low‐dose group, achieving a consistent 70% hepatic enzyme inhibition in subsequent ascending doses without any dose‐dependent effects. The unusual PK and PD profiles of BI 187004 suggest the presence of pharmacological target‐mediated drug disposition (TMDD), arising from the saturable binding of BI 187004 compound to its high‐affinity and low‐capacity target 11β‐HSD1. The non‐intuitive dose, exposure, and response relationship for BI 187004 pose a significant challenge in rational dose selection. This study aimed to construct a TMDD model to explain the complex nonlinear PK behavior and underscore the importance of recognizing TMDD in this small‐molecule compound. Among the various models explored, the best model was a two‐compartment TMDD model with three transit absorption components. The final model provides insights into 11β‐HSD1 binding‐related parameters for BI 187004, including the total amount of 11β‐HSD1 in the liver (estimated to be 8000 nmol), the second order association rate constant (estimated to be 0.102 nM−1h−1), and the first‐order dissociation rate constant (estimated to be 0.11 h−1). Our final population PK model successfully characterized the intricate nonlinear PK of BI 187004 across a wide dose range. This modeling work serves as a valuable reference for the rational selection of the dose regimens for BI 187004's future clinical trials. [ABSTRACT FROM AUTHOR]

In this work, for the first time, the specific impedances of various injection solutions as well as the surface and tissue impedance after injection of these solutions were analyzed and compared regarding the radio-frequency surgical cutting process. The impedances of 0.9% NaCl, 4% gelatine, 6% hydroxyethyl starch, 10% glycerol/5% fructose, 10% glucose, 5% and 20% albumin, blood, and blood plasma as well as aqua destillata have been tested in vitro. Even if EMR and ESD are routinely used in clinical practice, there is so far no easy, fast, and safe method to remove larger lesions en bloc. We show that the impedance of the injected solution shows to be a crucial factor for safe removal, especially of larger lesions (Ø > 20 mm) and more importantly in accordance with the requirements of oncology and pathology. Key messages: Impedance is playing a crucial factor in the radio-frequency (RF)-surgery. With a higher Impedance there will be less current necessary to reach the aimed voltage. Injection solution Aqua destillata and 10% Glucose, show significantly higher Impedances. Higher impedances lead to less surgical related complications. Minor changes in existing method to improve patent safety. [ABSTRACT FROM AUTHOR]

Introduction: The dose–response relationships of tacrolimus have been primarily assessed through trough concentrations during intermittent administrations. In scenarios where oral administration (PO) is unfeasible, continuous intravenous (IV) administration is advised. Under these circumstances, only steady-state (Css) plasma or blood concentrations are measured, with the absence of distinct trough levels (Cmin). Consequently, the measured concentrations are frequently misinterpreted as trough concentrations, potentially resulting in sub-therapeutic true tacrolimus blood levels. This study employs physiologically based pharmacokinetic modeling (PBPK) to establish the Css/Cmin ratio for tacrolimus across various clinical scenarios. Method: Using a validated PBPK model, the tacrolimus dose (both PO and IV) and the Css/Cmin ratios corresponding to matching area under the blood concentration–time curve during a dosage interval (AUCτ) values were estimated under different conditions, including healthy subjects and individuals exhibiting cytochrome P450 3A (CYP3A) interactions or CYP3A5 polymorphisms, along with a demonstration of a real-life clinical application. Result: In healthy volunteers, the oral/intravenous (PO/IV) dose ratio was found to be 4.25, and the Css/Cmin ratio was 1.40. A specific clinical case substantiated the practical applicability of the Css/Cmin ratio as simulated by PBPK, demonstrating no immediate clinical complications related to the transplant. When considering liver donors versus recipients expressing CYP3A5, the tacrolimus AUCτ was notably affected, yielding a PO/IV dose ratio of 4.00 and a Css/Cmin ratio of 1.75. Furthermore, the concomitant administration of the CYP3A inhibitor itraconazole given PO resulted in a PO/IV ratio of 1.75 with and a Css/Cmin ratio of 1.28. Notably, the inhibitory effect of itraconazole was diminished when administered IV. Conclusions: Through the application of PBPK methodologies, this study estimates the PO/IV dose ratios and Css/Cmin ratios that can enhance dose adjustment and therapeutic drug monitoring during the switch between IV and PO administration of tacrolimus in transplant patients, ultimately guiding clinicians in real-time decision-making. Further validation with in vivo data is recommended to support these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Some trace elements are essential for the health of vertebrates, but only limited data are available on blood levels in tortoises. The aim of this study was therefore to measure trace elements in heparinized blood plasma of Hermann's tortoises (Testudo hermanni) (n = 520) from March to September 2022 using inductively coupled plasma mass spectrometry (ICP-MS) and to establish specific reference intervals. Additionally, the influence of sex, season, and region of sample collection on the measured values were evaluated. Significant (p ≤ 0.05) sex-specific, seasonal, and regional differences were found for a number of trace elements indicating that all of these factors should be considered when establishing and interpreting blood trace element levels in tortoises. Some trace elements are essential for the health of vertebrates, but little is known about their function, the amounts required, and the factors influencing their metabolism in tortoises. The aim of this study was therefore to measure trace elements (chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), molybdenum (Mo), selenium (Se), zinc (Zn)) in heparinized blood plasma of Hermann's tortoises (Testudo hermanni) (n = 520) from March to September 2022 using inductively coupled plasma mass spectrometry (ICP-MS) and to establish specific reference intervals. Additionally, the influence of sex, season, and region of sample collection on the measured values were evaluated. Significant (p ≤ 0.05) sex-specific differences were found for Cu, Mg, and Mn; seasonal differences were found for Cr, Cu, Mn, Mo, and Se; and the region in which the tortoises were kept significantly impacted Cr, Cu, Fe, Mg, Mo, and Se levels. The results show that all of these factors should be consider when establishing and interpreting blood trace element levels in tortoises. [ABSTRACT FROM AUTHOR]

Exposure to ionizing radiation can result in the development of a number of diseases, including cancer, cataracts and neurodegenerative pathologies. Certain occupational groups are exposed to both natural and artificial sources of radiation as a consequence of their professional activities. The development of non-invasive biomarkers to assess the risk of exposure to ionizing radiation for these groups is of great importance. In this context, our objective was to identify epigenetic and molecular biomarkers that could be used to monitor exposure to ionizing radiation. The impact of X-ray exposure on the miRNAs profile and the level of cf mtDNA were evaluated using the RT-PCR method. The levels of pro-inflammatory cytokines in their blood were quantified using the ELISA method. A significant decrease in miR-19a-3p, miR-125b-5p and significant increase in miR-29a-3p was observed in the blood plasma of individuals exposed to X-ray. High levels of pro-inflammatory cytokines and cf mtDNA were also detected. In silico identification of potential targets of these miRNAs was conducted using MIENTURNET. VDAC1 and ALOX5 were identified as possible targets. Our study identified promising biomarkers such as miRNAs and cf mtDNA that showed a dose-dependent effect of X-ray exposure. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a leading cause of death, and this pathology often receives a diagnosis in an advanced stage. The development of a less invasive and cost-effective test for detection is essential for decreasing the mortality rate and increasing the life expectancy of GC patients. We evaluated the potential targeting of CD54/ICAM1, a marker of gastric cancer stem cells, with miRNAs to detect GC in blood samples. The analyses included 79 blood samples, 38 from GC patients and 41 from healthy donors, who attended INCan, México City. The total RNA was obtained from the blood plasma, and RT-PCR and qPCR were performed to obtain the relative expression of each miRNA. Hsa-miR-335-5p was detected in the plasma of GC patients and healthy donors at the same levels. The ROC curve analyses indicated that this miRNA was not a candidate for the molecular diagnosis of GC. We did not observe a correlation between the expression of hsa-miR-335-5p and clinical variables; however, the Kaplan–Meier analyses indicated that, in patients who survived more than 12 months, a lower expression of hsa-miR-335-5p was correlated with a better prognosis. It would be convenient to evaluate a larger panel of miRNAs, including miRNAs expressed in a limited number of cell types or with a low number targets, to obtain more specific candidates for developing a robust test for the diagnosis/prognosis of GC. [ABSTRACT FROM AUTHOR]

Context.--: The prothrombin time (PT) and activated partial thromboplastin time (APTT) are screening tests used to detect congenital or acquired bleeding disorders. An unexpected PT and/or APTT prolongation is often evaluated using a mixing test with normal plasma. Failure to correct ("noncorrection") prolongation upon mixing is attributed to an inhibitor, whereas "correction" points to factor deficiency(ies). Objective.--: To define an optimal method for determining correction or noncorrection of plasma mixing tests through an international, multisite study that used multiple PT and APTT reagents and well-characterized plasma samples. Design.--: Each testing site was provided 22 abnormal and 25 normal donor plasma samples, and mixing studies were performed using local PT and APTT reagents. Mixing study results were evaluated using 11 different calculation methods to assess the optimal method based on the expected interpretation for factor deficiencies (correction) and noncorrection (inhibitor effect). Misprediction, which represents the failure of a mixing study interpretation method, was assessed. Results.--: Percentage correction was the most suitable calculation method for interpreting PT mixing test results for nearly all reagents evaluated. Incubated PT mixing tests should not be performed. For APTT mixing tests, percentage correction should be performed, and if the result indicates a factor deficiency, this should be confirmed with the subtraction III calculation where the normal pooled plasma result (run concurrently) is subtracted from the mixing test result with correction indicated by a result of 0 or less. In general, other calculation methods evaluated that performed well in the identification of factor deficiency tended to have high misprediction rates for inhibitors and vice versa. Conclusions.--: No single method of mixing test result calculation was consistently successful in accurately distinguishing factor deficiencies from inhibitors, with between-reagent and between-site variability also identified. [ABSTRACT FROM AUTHOR]

Aim: Cisplatin is a highly effective anti‐cancer agent, but its clinical use is restricted due to severe renal toxicity. This study aimed to investigate the alleviative effects of juzentaihoto (JTT) in a mouse model of cisplatin‐induced renal injury. Methods: Four groups of seven‐week‐old male C57BL/6J mice (control, JTT, cisplatin, and JTT + cisplatin groups) were used in the study. The JTT and JTT + cisplatin groups received oral JTT (500 mg/kg) once a day for three days. After 24 h, the cisplatin, and JTT + cisplatin groups were intraperitoneally injected with cisplatin (15 mg/kg). The mice in each group were euthanized 72 h after cisplatin administration, and blood and kidney samples were collected. Results: Cisplatin injection decreased body weight and elevated plasma blood urea nitrogen and creatinine levels, while also increasing renal oxidative stress, inflammation, and cell death. These changes were alleviated by JTT administration. We also found that platinum accumulation in the kidneys following cisplatin injection was attenuated by JTT treatment. Furthermore, Mate1 expression levels (a cisplatin efflux transporter) were upregulated by JTT injection. Conclusion: Our results demonstrated that JTT mitigated cisplatin‐induced renal injury in mice by alleviating oxidative stress, inflammation, and cell death, achieved through the upregulation of the cisplatin efflux transporter Mate1. [ABSTRACT FROM AUTHOR]

During the gestation and lactation period, the energy demand in pregnant and lactating bitches is elevated. Non‐esterified fatty acids (NEFAs) are utilized either directly from the fed diet or from body fat storage. High NEFA concentration in the blood plasma leads to an increased risk for diseases. Therefore, measuring blood NEFA concentrations may be an indicator for a period of scarcity. The aim of this study is to explore if serum NEFA concentrations in healthy bitches change during gestation and lactation. Healthy pregnant and lactating bitches were sampled on three appointed dates around parturition. NEFA values were examined with a multiparameter clinical chemistry analyser. All statistical analyses were performed using R. Overall, 38 bitches were enrolled in the study. Twenty‐one bitches were sampled on all three appointed dates. The median NEFA concentration antepartum was 0.73 mmol/L (IQR: 0.59, 1.01); during peak lactation, it was 0.57 mmol/L (IQR: 0.44, 0.82); and around weaning, it was 0.58 mmol/L (IQR: 0.46, 0.73). NEFA concentrations rose slightly with litter size in late gestation. Body condition score had no influence on observed NEFA values. We conclude that NEFA concentrations widely remain within reference ranges in well‐fed pregnant and lactating bitches. Nevertheless, they may be a valuable parameter to assess the actual metabolic status of malnourished pregnant and lactating bitches. [ABSTRACT FROM AUTHOR]

Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed/refractory (R/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20 mg once daily (OD) to 210 mg OD without DLT, but gastrointestinal DLTS were seen in the 280 mg cohort. MTD and recommended phase 2 dose were 210 mg OD. Common adverse events were predominantly Gr ≤ 2 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2 h with terminal half-lives averaging 10 h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210 mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) could be a condition underlying several human diseases, despite the physiological role of reactive oxygen species (oxidative eustress). Therefore, antioxidant compounds could represent a modulatory mechanism for maintaining a proper redox balance and redox signaling. When antioxidants are insufficient or overwhelmed, OS ensues, causing multiple damages at molecular, tissue, and cellular levels. This study focuses on the role of total antioxidant capacity (TAC) as a biomarker to be interpreted according to several clinical scenarios. After a brief description of various assay methods to elucidate terminology and physiopathological roles, we focus on the hormonal influence on TAC in blood plasma and other biological fluids, as different endocrine systems can modulate the antioxidant response. Furthermore, OS characterizes several endocrinopathies through different mechanisms: an inadequate antioxidant response to an increase in reducing equivalents (reductive distress) or a marked consumption of antioxidants (oxidative distress), which leads to low TAC values. An increased TAC could instead represent an adaptive mechanism, suggesting a situation of OS. Hence, the clinical context is fundamental for a correct interpretation of TAC. This review aims to provide the reader with a general overview of oxidative stress in several clinical examples of endocrine relevance, such as metabolic syndrome, non-thyroid illness syndrome, hypopituitarism, and infertility. Finally, the impact of dietary and surgical interventions on TAC in the model of metabolic syndrome is highlighted, along with personal experience. [ABSTRACT FROM AUTHOR]

The study aimed to investigate the impact of wet feeding on broiler chicken performance and intestinal histomorphometry. The research was conducted at the Veterinary College, Udaipur, India, using 144 commercial broiler chicks from day 1 to 6 weeks of age. The chicks were divided randomly into three experimental groups, each with four replicates comprising 48 birds. The control group (G1) was fed dry; while, group 2 (G2) received wet feed supplemented with 1.00 g water per g of feed and group 3 (G3) received wet feed supplemented with 1.20 g water per g of feed. Results revealed that G3 had significantly superior feed conversion ratios, lower feed intake, and increased body weight and weight gain compared to G2 and G1. Among the three treatment groups, there were no variations in blood plasma indicators. In comparison with G1, duodenum and ileum in G2 had higher villus height. The G3 revealed higher net profit margins and 18.89% saving of feed compared to G1, suggesting that it may be a valuable tool for lowering chicken feed costs. [ABSTRACT FROM AUTHOR]

Magnetotactic bacteria (MTB) are promising candidates for use as biomicrorobots in biomedical applications due to their motility, self-propulsion, and the ability to direct their navigation with an applied magnetic field. When in the body, the MTB may encounter non-Newtonian fluids such as blood plasma or mucus. However, their motility and the effectiveness of directed navigation in non-Newtonian fluids has yet to be studied on a single-cell level. In this work, we investigate motility of Magnetospirillum magneticum AMB-1 in three concentrations of polyacrylamide (PAM) solution, a mucus-mimicking fluid. The swimming speeds increase from 44.0 ± 13.6 µm/s in 0 mg/mL of PAM to 52.73 ± 15.6 µm/s in 1 mg/mL then decreases to 24.51 ± 11.7 µm/s in 2 mg/mL and 21.23 ± 10.5 µm/s in 3 mg/mL. This trend of a speed increase in low polymer concentrations followed by a decrease in speed as the concentration increases past a threshold concentration is consistent with other studies of motile, flagellated bacteria. Past this threshold concentration of PAM, there is a higher percentage of cells with an overall trajectory angle deviating from the angle of the magnetic field lines. There is also less linearity in the trajectories and an increase in reversals of swimming direction. Altogether, we show that MTB can be directed in polymer concentrations mimicking biological mucus, demonstrating the influence of the medium viscosity on the linearity of their trajectories which alters the effective path that could be predefined in Newtonian fluids when transport is achieved by magnetotaxis. [ABSTRACT FROM AUTHOR]