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Toxics Apr 2024Obesity, a chronic metabolic disorder, is related to cardiovascular diseases, diabetes, cancer, and reproductive disorders. The relationship between obesity and male...
BACKGROUND
Obesity, a chronic metabolic disorder, is related to cardiovascular diseases, diabetes, cancer, and reproductive disorders. The relationship between obesity and male infertility is now well recognized, but the mechanisms involved are unclear. We aimed to observe the effect of obesity on spermatogenesis and to investigate the role of histone ubiquitination and acetylation modifications in obesity-induced spermatogenesis disorders.
METHODS
Thirty male C57BL/6J mice were randomly divided into two groups. The control group was fed with a general maintenance diet (12% fat), while a high-fat diet (HFD) group was fed with 40% fat for 10 weeks; then, they were mated with normal females. The fertility of male mice was calculated, testicular and sperm morphology were observed, and the expression levels of key genes and the levels of histone acetylation and ubiquitination modification during spermatogenesis were detected.
RESULTS
The number of sperm was decreased, as well as the sperm motility, while the number of sperm with malformations was increased. In the testes, the mRNA and protein expression levels of gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), chromosome region maintenance-1 protein (CRM1), high-mobility group B2 (HMGB2), phosphoglycerate kinase 2 (PGK2), and testicular angiotensin-converting enzyme (tACE) were decreased. Furthermore, obesity led to a decrease in ubiquitinated H2A (ubH2A) and reduced levels of histone H3 acetylation K18 (H3AcK18) and histone H4 acetylation K5, K8, K12, and K16 (H4tetraAck), which disrupted protamine 1 (Prm1) deposition in testis tissue.
CONCLUSION
These results suggest that low levels of histone ubiquitination and acetylation are linked with obesity-induced disorders during spermatogenesis, contributing to a better understanding of obesity-induced damage to male reproduction.
PubMed: 38668519
DOI: 10.3390/toxics12040296 -
International Journal of Endocrinology... Oct 2023Type 1 diabetes mellitus (T1DM) is a prevalent chronic disease among children and adolescents, necessitating effective self-monitoring of blood glucose (SMBG) levels....
BACKGROUND
Type 1 diabetes mellitus (T1DM) is a prevalent chronic disease among children and adolescents, necessitating effective self-monitoring of blood glucose (SMBG) levels. Understanding the determinants and factors influencing SMBG behavior is crucial for optimizing diabetes management in this population.
OBJECTIVES
This study aimed to investigate the frequency of SMBG and identify the determinants influencing factors in children and adolescents with T1DM.
METHODS
This cross-sectional study was conducted in Tehran, Iran, and included 275 participants selected through simple random sampling from the Gabric Diabetes Education Association. The inclusion criteria comprised children and adolescents aged 3 - 18 years diagnosed with T1DM for at least 6 months who were using analog or neutral protamine Hagedorn (NPH) and regular insulin subcutaneously. Patients using insulin pumps were excluded. Data collection involved an online questionnaire covering demographic information (e.g., age, gender, educational status, and parental occupations) as well as clinical information (number of hypoglycemic episodes, hemoglobin A1C (HbA1C) levels, diabetes duration, insulin regimen, diabetes complications, glucose monitoring practices, hospitalizations, and behavioral characteristics). Statistical analyses, including descriptive statistics, correlation tests, and Poisson regressions, were performed using SPSS software (version 21). A significance level of P-value < 0.05 was considered statistically significant.
RESULTS
The participants had a mean age of 10.00 ± 3.77 years, with 54.2% being males. Most of the participants (87.3%) were schoolchildren, and the mean age of diagnosis was 6.56 ± 3.73 years, with a mean duration of 44.72 ± 36.32 months. Anthropometric investigations revealed mean height, weight, and body mass index (BMI) values of 136.69 ± 21.11 cm, 37.45 ± 15.51 kg, and 18.31 ± 3.55 kg/m, respectively. The majority of participants (93.5%) used insulin pens, and the mean daily insulin dosage was 35.34 ± 22.20 IU. Parents reported consistent glucose level monitoring in 64.7% of cases. The mean HbA1c level was 7.91 ± 1.58%. Factors such as the price and availability of glucometer strips influenced glucose level monitoring. In univariate analysis, only age and HbA1C levels showed a negative correlation; however, parents' consistent checking showed a positive correlation with the frequency of daily, weekly, or monthly glucose checking.
CONCLUSIONS
This study underscores the significance of SMBG in children and adolescents with T1DM. The findings emphasize the critical role of price and availability of glucometers and strips in achieving standard care for T1DM patients.
PubMed: 38666044
DOI: 10.5812/ijem-138377 -
Journal of Diabetes May 2024The study aimed to compare glycemic control and pregnancy outcomes in women with type 1 diabetes mellitus (T1DM) using multiple daily injection therapy (MDI) and... (Comparative Study)
Comparative Study
INTRODUCTION
The study aimed to compare glycemic control and pregnancy outcomes in women with type 1 diabetes mellitus (T1DM) using multiple daily injection therapy (MDI) and continuous subcutaneous insulin infusion (CSII) and to compare outcomes of women treated with long-acting insulin or neutral protamine Hagedorn (NPH).
METHODS
This multicenter prospective cohort study involved women with pregestational T1DM treated with MDI and CSII. Primary outcome was glycated hemoglobin (HbA1c) before and during pregnancy. Secondary outcomes included maternal and neonatal outcomes and quality of life.
RESULTS
Of the 121 studied women, the average age was 28.48 years, and the average body mass index was 21.29 kg/m at conception and 26.32 kg/m at delivery. Of the studied women, 78.51% had planned pregnancy. Women treated with MDI and CSII had comparable HbA1c before pregnancy or in the first and second trimesters. In the third trimester, women on CSII therapy had significantly lower HbA1c (6.07 ± 0.62 vs 6.20 ± 0.88%, p = .017), higher HbA1c on-target rate (71.43% vs 64.62%, p = .030), and greater decline of HbA1c from preconception to the third trimester (-0.65 vs -0.30%, p = .047). Fewer daily insulin requirements were observed in those used CSII compared with MDI-treated women (0.60 ± 0.22 vs 0.73 ± 0.25 U/kg/day, p = .004). Newborns born of mothers treated with the CSII method were more likely to have neonatal jaundice (adjusted odds ratio [OR] 2.76, 95% confidence interval [CI] 1.16-6.57) and neonatal intensive care unit (adjusted OR 3.73, 95%CI 1.24-11.16), and women on CSII had lower scores in patient-reported quality of life (p = .045). In the MDI group, those receiving long-acting insulin had nonsignificant lower HbA1c and higher HbA1c on-target rate in the second and third trimesters, compared with those treated with NPH.
CONCLUSIONS
Insulin pump users may achieve better glycemic control than multiple daily insulin injections, which did not substantially improve pregnancy outcome.
Topics: Humans; Female; Pregnancy; Diabetes Mellitus, Type 1; Adult; Insulin; Insulin Infusion Systems; Prospective Studies; Hypoglycemic Agents; Pregnancy in Diabetics; Injections, Subcutaneous; Glycated Hemoglobin; Pregnancy Outcome; Infusions, Subcutaneous; Blood Glucose; Quality of Life; Glycemic Control
PubMed: 38664886
DOI: 10.1111/1753-0407.13558 -
Clinical and Applied... 2024Andexanet alfa (AA) - zhzo, recombinant coagulation factor Xa, is an approved antidote for oral Xa inhibitors (apixaban and rivaroxaban). Unfractionated heparin (UFH) is...
INTRODUCTION
Andexanet alfa (AA) - zhzo, recombinant coagulation factor Xa, is an approved antidote for oral Xa inhibitors (apixaban and rivaroxaban). Unfractionated heparin (UFH) is commonly used for therapeutic, interventional, and surgical indications. Protamine sulfate (PrSO) is frequently used to neutralize UFH. This study aimed to investigate the comparative neutralization profiles of AA and PrSO for heparins of bovine, ovine, and porcine origin.
MATERIALS AND METHODS
The neutralization effect of PrSO at 25 µg/ml and AA at 100 µg/ml was studied on an approximate surgical/interventional concentration of heparin by supplementing whole blood with each of the heparins at 25 µg/ml. For the clotting profile (activated partial thromboplastin time: aPTT), amidolytic (anti-Xa and anti-IIa), and thrombin generation assay each of the heparin were supplemented from -10-0.62 µg/ml.
RESULTS
In the whole blood ACT studies, all three heparins produced strong anti-coagulant effects (400-450 seconds) compared to saline (130-150 seconds). Both AA and PrSO almost fully neutralized the anti-coagulant effects of heparins (140-160 seconds). Both antidotes completely reversed the anticoagulant effects of all three heparins in the aPTT and thrombin generation assay. However, PrSO was more effective in neutralizing the anti-Xa, and anti-IIa effects than AA, which only partially neutralized these effects.
CONCLUSION
Andexanet alfa at 100 µg/ml effectively neutralizes the therapeutic and surgical/interventional concentrations of heparins in settings. While differences in the anti-Xa, and anti-IIa effects between heparins were noted, anti-coagulant effect of these agents in the aPTT assay were comparable. A similar neutralization profile was observed in the ACT and thrombin generation assays by both agents.
Topics: Recombinant Proteins; Factor Xa; Cattle; Sheep; Swine; Animals; Anticoagulants; Heparin; Protamines; Heparin Antagonists; Blood Coagulation; Thrombin Time
PubMed: 38656136
DOI: 10.1177/10760296241247558 -
Annals of Internal Medicine May 2024In the United States, costs of antidiabetes medications exceed $327 billion. (Review)
Review
Cost-Effectiveness of Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Systematic Review of Cost-Effectiveness Studies for the American College of Physicians.
BACKGROUND
In the United States, costs of antidiabetes medications exceed $327 billion.
PURPOSE
To systematically review cost-effectiveness analyses (CEAs) of newer antidiabetes medications for type 2 diabetes.
DATA SOURCES
Bibliographic databases from 1 January 2010 through 13 July 2023, limited to English.
STUDY SELECTION
Nonindustry-funded CEAs, done from a U.S. perspective that estimated cost per quality-adjusted life-year (QALY) gained for newer antidiabetic medications. Two reviewers screened the literature; disagreements were resolved with a third reviewer.
DATA EXTRACTION
Cost-effectiveness analyses were reviewed for treatment comparisons, model inputs, and outcomes. Risk of bias (RoB) of the CEAs was assessed using Drummond criteria and certainty of evidence (CoE) was assessed using GRADE (Grading of Recommendations Assessment, Development, and Evaluations). Certainty of evidence was determined using cost per QALY thresholds predetermined by the American College of Physicians Clinical Guidelines Committee; low (>$150 000), intermediate ($50 to $150 000), or high (<$50 000) value per QALY compared with the alternative.
DATA SYNTHESIS
Nine CEAs were eligible (2 low, 1 high, and 6 some concerns RoB), evaluating glucagon-like peptide-1 agonists (GLP1a), dipeptidyl peptidase-4 inhibitors (DPP4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucose-dependent insulinotropic peptide agonist (GIP/GLP1a), and insulin. Comparators were metformin, sulfonylureas, neutral protamine Hagedorn (NPH) insulin, and others. Compared with metformin, GLP1a and SGLT2i are low value as first-line therapy (high CoE) but may be of intermediate value when added to metformin or background therapy compared with adding nothing (low CoE). Insulin analogues may be similarly effective but more expensive than NPH insulin (low CoE). The GIP/GLP1a value is uncertain (insufficient CoE).
LIMITATIONS
Cost-effectiveness analyses varied in methodological approach, assumptions, and drug comparisons. Risk of bias and GRADE method for CEAs are not well established.
CONCLUSION
Glucagon-like peptide-1 agonists and SGLT2i are of low value as first-line therapy but may be of intermediate value when added to metformin or other background therapy compared with adding nothing. Other drugs and comparisons are of low or uncertain value. Results are sensitive to drug effectiveness and cost assumptions.
PRIMARY FUNDING SOURCE
American College of Physicians. (PROSPERO: CRD42022382315).
Topics: Diabetes Mellitus, Type 2; Humans; Cost-Benefit Analysis; Hypoglycemic Agents; Quality-Adjusted Life Years; United States; Dipeptidyl-Peptidase IV Inhibitors; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 38639547
DOI: 10.7326/M23-1492 -
Journal of Cardiothoracic Surgery Apr 2024Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and...
BACKGROUND
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a severe adverse drug reaction marked by delayed hypersensitivity reactions causing skin and systemic complications. DRESS diagnosis is challenging due to the variety of clinical presentations and symptom overlap with other conditions. The perioperative period in these patients requires precise pharmacological strategies to prevent complications associated with this syndrome. The treatment of DRESS induced by unfractionated heparin during cardiopulmonary bypass (CPB) surgery presents some challenges that must be considered when selecting an anticoagulant to avoid side effects. In this case, bivalirudin, a direct thrombin inhibitor, is indicated as an alternative to heparin in patients undergoing CPB. However, in contrast to heparin/protamine, there is no direct reversal agent for bivalirudin.
CASE PRESENTATION
We report the case of an 11-year-old male diagnosed with native aortic valve endocarditis and thrombosis in his left lower extremity. During valvular replacement surgery, systemic unfractionated heparin was administered. Postoperatively, the patient developed fever, eosinophilia and pruritic rash. Warm shock and elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels followed, leading to the diagnosis of DRESS syndrome. Treatment with methylprednisolone resulted in complete resolution of symptoms. Seven years later, the patient was readmitted due to insufficient anticoagulation and a thrombus in the prosthetic aortic valve, presenting a recurrent DRESS episode due to the administration of unfractionated heparin, which was later replaced with low-molecular-weight heparin during hospitalization. Treatment with corticosteroids and antihistamines was initiated, resulting in the resolution of this episode. Ultimately, the patient required the Ross procedure. During this intervention the anticoagulation strategy was modified, unfractionated heparin was replaced with bivalirudin during the procedure and fondaparinux was administered during the postoperative period. This resulted in stable transaminases levels and no eosinophilia.
CONCLUSION
The severity of DRESS Syndrome underscores the importance of early recognition, heightened monitoring, and a comprehensive approach tailored to each patient's needs. This particular case highlights the significance of this approach and may have a substantial clinical impact since it provides alternatives to heparin, such as bivalirudin and fondaparinux, in the anticoagulation strategy of CPB for patients who have a hypersensibility reaction to this medication; thus, enhancing clinical outcomes by minimizing risks linked to adverse drug reactions.
Topics: Male; Humans; Child; Heparin; Fondaparinux; Drug Hypersensitivity Syndrome; Anticoagulants; Hirudins; Eosinophilia; Peptide Fragments; Anesthetics; Recombinant Proteins
PubMed: 38632589
DOI: 10.1186/s13019-024-02722-x -
Cell Journal Mar 2024Celiac disease is a common chronic inflammatory condition of the small intestine caused by permanent intolerance to gluten/gliadin. It has been demonstrated that...
OBJECTIVE
Celiac disease is a common chronic inflammatory condition of the small intestine caused by permanent intolerance to gluten/gliadin. It has been demonstrated that oxidative stress is one of the mechanisms that is involved in gliadin toxicity, and there is a correlation between oxidative damage with this disease. Similarly, increased oxidative stress was repeatedly reported in infertile men which led to low-quality of sperm function. Therefore, we aimed to assess sperm parameters and chromatin status in men with Celiac disease.
MATERIALS AND METHODS
In this case-control study, semen samples were collected from 11 fertile men without Celiac and 10 men with diagnostic Celiac disease. Basic semen analyses were performed according to the World Health Organization (WHO) 2010 protocol. The percentage of sperm with persistence histones, protamine deficiency, DNA fragmentation, malondialdehyde (MDA), and intracellular reactive oxygen species (ROS) were assessed using aniline blue, chromomycin A3, sperm chromatin structure assay, thiobarbituric acid reactive substances (TBARS) assay, and diacetyldichlorofluorescein staining, respectively.
RESULTS
Unlike the sperm parameters, which did not show significant differences between men with Celiac disease and fertile individuals, sperm chromatin maturation (persistence histones and protamine deficiency) and sperm DNA damage in men with Celiac disease were significantly higher compared to fertile individuals (P<0.05). In addition, the percentage of sperm viability in these individuals was significantly lower than that in the fertile individuals (P<0.05). We did not observe any significant differences in sperm lipid peroxidation and intracellular ROS levels between the two study groups (P>0.05).
CONCLUSION
Celiac disease affects sperm chromatin maturation and DNA fragmentation, emphasizing its impact on reproductive health.
PubMed: 38628093
DOI: 10.22074/cellj.2024.2014048.1432 -
Langmuir : the ACS Journal of Surfaces... Apr 2024In this study, we proposed a method for fabricating Janus sheets using biological "microflowers" as a sacrificial template. The microflower-templated Janus sheets...
In this study, we proposed a method for fabricating Janus sheets using biological "microflowers" as a sacrificial template. The microflower-templated Janus sheets (MF-JNSs) were employed as a foam stabilizer in foam separation of the whey soybean protein (WSP). The MF-JNSs took inorganic hybrid microflowers (BSA@Cu (PO)-MF) as template, followed by the sequential attachment of protamine and silica to the surface of the BSA@Cu(PO)-MF. Subsequently, the template was removed using ethylenediaminetetraacetic acid after the silicon dioxide was modified by 3-(methacryloyloxy) propyl trimethoxysilane. Upon template dissolution, the modified silica layer, lacking support from the core, fractured to form the MF-JNSs. This method omitted the step of treating the hollow ball by external force and obtained Janus sheets in one step, indicating that it was simple and feasible. The morphology, structure, and composition of the MF-JNSs were analyzed by SEM, TEM, AFM, XRD, and FT-IR. The MF-JNSs were found to delay the breakage time of the Pickering emulsion, demonstrating their emulsion stabilizing capability. Importantly, they significantly enhanced the foam half-life and foam height of soybean whey wastewater (SWW). Moreover, the recovery percentage and enrichment ratio of WSP, separated from SWW by foam separation, were improved to 81 ± 0.28 and 1.20 ± 0.05%, respectively.
PubMed: 38627903
DOI: 10.1021/acs.langmuir.4c00239 -
Biochimica Et Biophysica Acta.... Jun 2024Protamine, an antimicrobial protein derived from salmon sperm with a molecular weight of approximately 5 kDa, is composed of 60-70 % arginine and is a highly charged...
Protamine, an antimicrobial protein derived from salmon sperm with a molecular weight of approximately 5 kDa, is composed of 60-70 % arginine and is a highly charged protein. Here, we investigated the mechanism of antimicrobial action of protamine against Cutibacterium acnes (C. acnes) focusing on its rich arginine content and strong positive charge. Especially, we focused on the attribution of dual mechanisms of antimicrobial protein, including membrane disruption or interaction with intracellular components. We first determined the dose-dependent antibacterial activity of protamine against C. acnes. In order to explore the interaction between bacterial membrane and protamine, we analyzed cell morphology, zeta potential, membrane permeability, and the composition of membrane fatty acid. In addition, the localization of protamine in bacteria was observed using fluorescent-labeled protamine. For investigation of the intracellular targets of protamine, bacterial translation was examined using a cell-free translation system. Based on our results, the mechanism of the antimicrobial action of protamine against C. acnes is as follows: 1) electrostatic interactions with the bacterial cell membrane; 2) self-internalization into the bacterial cell by changing the composition of the bacterial membrane; and 3) inhibition of bacterial growth by blocking translation inside the bacteria. However, owing to its strong electric charge, protamine can also interact with DNA, RNA, and other proteins inside the bacteria, and may inhibit various bacterial life processes beyond the translation process.
Topics: Protamines; Arginine; Cell Membrane; Animals; Anti-Bacterial Agents; Static Electricity; Cell Membrane Permeability; Microbial Sensitivity Tests
PubMed: 38614236
DOI: 10.1016/j.bbamem.2024.184323 -
Biomaterials Jul 2024Frequent injections of anti-CD124 monoclonal antibody (αCD124) over long periods of time are used to treat chronic rhinosinusitis with nasal polyps (CRSwNP)....
Frequent injections of anti-CD124 monoclonal antibody (αCD124) over long periods of time are used to treat chronic rhinosinusitis with nasal polyps (CRSwNP). Needle-free, intranasal administration (i.n.) of αCD124 is expected to provide advantages of localized delivery, improved efficacy, and enhanced medication adherence. However, delivery barriers such as the mucus and epithelium in the nasal tissue impede penetration of αCD124. Herein, two novel protamine nanoconstructs: allyl glycidyl ether conjugated protamine (Nano-P) and polyamidoamine-linked protamine (Dendri-P) were synthesized and showed enhanced αCD124 penetration through multiple epithelial layers compared to protamine in mice. αCD124 was mixed with Nano-P or Dendri-P and then intranasally delivered for the treatment of severe CRSwNP in mice. Micro-CT and pathological changes in nasal turbinates showed that these two nano-formulations achieved ∼50 % and ∼40 % reductions in nasal polypoid lesions and eosinophil count, respectively. Both nano-formulations provided enhanced efficacy in suppressing nasal and systemic Immunoglobulin E (IgE) and nasal type 2 inflammatory biomarkers, such as interleukin 13 (IL-13) and IL-25. These effects were superior to those in the protamine formulation group and subcutaneous (s.c.) αCD124 given at a 12.5-fold higher dose. Intranasal delivery of protamine, Nano-P, or Dendri-P did not induce any measurable toxicities in mice.
Topics: Animals; Female; Mice; Administration, Intranasal; Antibodies, Monoclonal; Chronic Disease; Mice, Inbred BALB C; Nasal Polyps; Protamines; Rhinosinusitis
PubMed: 38603825
DOI: 10.1016/j.biomaterials.2024.122567