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Journal of the International AIDS... Jun 2024Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)-based antiretroviral therapy (ART) experience greater weight...
INTRODUCTION
Outside of pregnancy, evidence shows that persons with HIV initiating or switching to dolutegravir (DTG)-based antiretroviral therapy (ART) experience greater weight gain compared to those on other ART classes. However, there are few data on the impact of DTG-based ART on gestational weight gain (GWG) in sub-Saharan Africa where HIV is most common. According to the National Academy of Medicine (NAM), GWG below and above NAM guidelines is associated with adverse birth outcomes. Therefore, the objective of this study was to describe GWG by HIV status and ART regimen, and examine the associations with adverse birth outcomes.
METHODS
We enrolled pregnant women with HIV (WHIV) and without HIV (≥18 years) in a peri-urban primary healthcare facility in Cape Town, South Africa between 2019 and 2022. GWG was study-measured at 24-28 (baseline) and 33-38 weeks gestation and converted to GWG rate (kg/week) in accordance with NAM guidelines. GWG z-scores were generated using the INTEGROWTH-21 and US standards to account for differing lengths of gestation. Birth outcome data were obtained from medical records. Associations of GWG z-score with adverse birth outcomes were assessed using multivariable linear or log-binomial regression.
RESULTS
Among 292 participants (48% WHIV), median age was 29 years (IQR, 25-33), median pre-pregnancy body mass index (BMI) was 31 kg/m (IQR, 26-36) and 20% were primiparous at baseline. The median weekly rate of GWG was 0.30 kg/week (IQR, 0.12-0.50), 35% had GWG below NAM standards (59% WHIV) and 48% had GWG above NAM standards (36% WHIV). WHIV gained weight more slowly (0.25 vs. 0.37 kg/week, p<0.01) than women without HIV. Weekly rate of GWG did not differ by ART regimen (DTG-based ART 0.25 vs. efavirenz-based ART 0.27 kg/week, p = 0.80). In multivariable analyses, GWG z-score was positively associated with continuous birth weight (mean difference = 68.53 95% CI 8.96, 128.10) and categorical high birth weight of >4000 g (RR = 2.18 95% CI 1.18, 4.01).
CONCLUSIONS
Despite slower GWG among WHIV, nearly half of all women gained weight faster than recommended by the NAM. GWG was positively associated with infant birth weight. Interventions to support healthy GWG in sub-Saharan Africa are urgently needed.
Topics: Humans; Female; Pregnancy; HIV Infections; Adult; South Africa; Prospective Studies; Gestational Weight Gain; Pregnancy Complications, Infectious; Young Adult; Pregnancy Outcome; Infant, Newborn; Pyridones; Oxazines; Anti-HIV Agents; Heterocyclic Compounds, 3-Ring; Piperazines
PubMed: 38926935
DOI: 10.1002/jia2.26313 -
Journal of Nanobiotechnology Jun 2024The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell...
BACKGROUND
The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/β-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application.
RESULTS
The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest.
CONCLUSIONS
The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization.
Topics: Exosomes; Wound Healing; Mesenchymal Stem Cells; Humans; Animals; Wnt Signaling Pathway; Mice; Umbilical Cord; Pyridines; Diabetes Mellitus, Experimental; Pyrimidines; Male; Cells, Cultured; Cell Movement
PubMed: 38926800
DOI: 10.1186/s12951-024-02650-x -
Journal of Medical Case Reports Jun 2024Insulin autoantibody syndrome (IAS), or Hirata disease, is caused by high concentrations of insulin autoantibodies, which result in spontaneous, mainly post-prandial,...
BACKGROUND
Insulin autoantibody syndrome (IAS), or Hirata disease, is caused by high concentrations of insulin autoantibodies, which result in spontaneous, mainly post-prandial, hypoglycemic episodes. We report a case of a previously healthy 67-year-old man presenting with recurrent fasting hypoglycemia culminating in a diagnosis of insulin autoimmune syndrome linked to omeprazole and probably spices, namely, coriander, and ginger.
CASE PRESENTATION
A previously healthy 67-year-old Sinhalese man presented with recurrent syncopal attacks for 3 months, which were found to be hypoglycemic episodes. He experienced mainly fasting hypoglycemic attacks, at a frequency gradually increasing to daily attacks. His cardiovascular, respiratory, abdominal, and neurologic examinations were normal. He was found to have insulin levels > 6000 mU/L and a post-polyethylene glycol insulin recovery of less than 9.5%. Contrast-enhanced computed tomography of the pancreas was normal. The diagnosis of insulin autoantibody syndrome was confirmed by testing for the insulin autoantibody level, yielding a level of > 300 U/mL. With regard to a possible trigger, he had a history of omeprazole intake for 2 weeks, 4 weeks prior to the onset of symptoms. He also consumed an herbal supplement containing coriander and ginger extracts daily for a period of 1 year, approximately 2 years prior to the onset of hypoglycemic attacks. He was commenced on prednisolone 30 mg daily, and hypoglycemic episodes responded dramatically, and thus he was tapered off corticosteroids.
CONCLUSION
Omeprazole-induced insulin autoantibody syndrome is likely in this patient; however, the known hypoglycemic effects of coriander and ginger make it worthwhile to consider a possible association with insulin autoantibody syndrome. In addition, this case report highlights the need to consider insulin autoantibody syndrome even in patients presenting with fasting hypoglycemic attacks.
Topics: Humans; Male; Aged; Hypoglycemia; Insulin Antibodies; Omeprazole; Autoimmune Diseases; Insulin; Zingiber officinale; Syndrome; Autoantibodies
PubMed: 38926797
DOI: 10.1186/s13256-024-04616-x -
BMC Neuroscience Jun 2024Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This...
BACKGROUND
Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin-angiotensin-aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons.
RESULT
The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes.
CONCLUSION
Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context.
Topics: Animals; Astrocytes; Rats, Wistar; Microglia; Receptor, Angiotensin, Type 2; Telmisartan; Angiotensin II Type 1 Receptor Blockers; Neurons; Receptor, Angiotensin, Type 1; Ischemic Stroke; Angiotensin II Type 2 Receptor Blockers; Rats; Cells, Cultured; Pyridines; Imidazoles; Animals, Newborn; Benzimidazoles; Cell Communication
PubMed: 38926677
DOI: 10.1186/s12868-024-00876-x -
Biological & Pharmaceutical Bulletin 2024Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are...
Unknown interactions between drugs remain the limiting factor for clinical application of drugs, and the induction and inhibition of drug-metabolizing CYP enzymes are considered the key to examining the drug-drug interaction (DDI). In this study, using human HepaRG cells as an in vitro model system, we analyzed the potential DDI based on the expression levels of CYP3A4 and CYP1A2. Rifampicin and omeprazole, the potent inducers for CYP3A4 and CYP1A2, respectively, induce expression of the corresponding CYP enzymes at both the mRNA and protein levels. We noticed that, in addition to inducing CYP1A2, omeprazole induced CYP3A4 mRNA expression in HepaRG cells. However, unexpectedly, CYP3A4 protein expression levels were not increased after omeprazole treatment. Concurrent administration of rifampicin and omeprazole showed an inhibitory effect of omeprazole on the CYP3A4 protein expression induced by rifampicin, while its mRNA induction remained intact. Cycloheximide chase assay revealed increased CYP3A4 protein degradation in the cells exposed to omeprazole. The data presented here suggest the potential importance of broadening the current DDI examination beyond conventional transcriptional induction and enzyme-activity inhibition tests to include post-translational regulation analysis of CYP enzyme expression.
Topics: Omeprazole; Humans; Cytochrome P-450 CYP3A; Rifampin; RNA, Messenger; Drug Interactions; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP1A2; Cell Line
PubMed: 38925922
DOI: 10.1248/bpb.b24-00161 -
Anticancer Research Jul 2024Sorafenib and lenvatinib have long been used as a first-line treatment for advanced hepatocellular carcinoma (HCC). Along with the development of systemic chemotherapy...
BACKGROUND/AIM
Sorafenib and lenvatinib have long been used as a first-line treatment for advanced hepatocellular carcinoma (HCC). Along with the development of systemic chemotherapy for HCC, the concept of conversion hepatectomy has recently become widespread. The present study aimed to assess the clinical outcomes of sorafenib and lenvatinib for HCC regarding the possibility of conversion hepatectomy in clinical practice.
PATIENTS AND METHODS
A total of 295 patients with advanced HCC receiving sorafenib and lenvatinib, accounting for 306 treatments (sorafenib, n=157; lenvatinib, n=149, 11 patients received lenvatinib after sorafenib treatment) at five different institutions were enrolled. Patients were assessed for their clinical characteristics and therapeutic response using both Response Evaluation Criteria in Solid Tumors criteria (RECIST) and modified RECIST (mRECIST) criteria. Additionally, an indication of surgery after tyrosine kinase inhibitor administration was determined based on the tumor status of patients.
RESULTS
The median survival times of patients treated with sorafenib and lenvatinib were 12.8 and 16.4 months, respectively, without significant difference (p=0.1645). The objective response rates (ORR) of sorafenib based on mRECIST and RECIST were 10.1% and 5.9%, respectively, and those of lenvatinib were 38.1% and 19.0%, respectively. Among the 306 treatments, two cases (sorafenib and lenvatinib, one each) underwent hepatectomy after systemic chemotherapy.
CONCLUSION
Few cases with unresectable HCC were amenable to conversion hepatectomy after sorafenib and lenvatinib treatments due to the limited ORR by RECIST. Cautious approach must be taken when administering neoadjuvant chemotherapy aimed at conversion hepatectomy.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Quinolines; Phenylurea Compounds; Sorafenib; Male; Female; Hepatectomy; Middle Aged; Aged; Adult; Aged, 80 and over; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 38925835
DOI: 10.21873/anticanres.17123 -
BMJ Open Jun 2024Insomnia is a common health problem and cognitive-behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Insomnia is a common health problem and cognitive-behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we developed a digital CBT application (IIIP MED: Sleepy Med) as Software as a Medical Device for insomnia. This paper describes the study protocol for an exploratory randomised controlled trial (RCT) to evaluate effectiveness and safety of our developed digital CBT (dCBT) for 5 weeks compared with zolpidem tartrate for patients with insomnia disorder.
METHODS AND ANALYSIS
This proposed multicentre exploratory RCT will be conducted at the outpatient clinic of Chiba University Hospital, Akita University Hospital and Yoyogi Sleep Disorder Center, Japan. The study population comprises two parallel groups (dCBT and zolpidem) consisting of 15 participants each (n=30 in total) diagnosed with insomnia disorder who remain symptomatic at 4 weeks after sleep hygiene education. We will evaluate the effectiveness at baseline, week 5 (post-intervention) and week 10 (follow-up). The primary outcome will be the change of subjective sleep onset latency at week 5 from baseline. Secondary outcomes include sleep-related outcomes, such as objective sleep onset latency measured by mobile electroencephalography, functional improvement during the daytime and quality of life.
ETHICS AND DISSEMINATION
Ethics approval was granted by the Institutional Review Board of Chiba University Hospital (K2023001). All participants will be required to provide written informed consent. Results will be published in international journals.
TRIAL REGISTRATION NUMBER
jRCT2032230353.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Zolpidem; Cognitive Behavioral Therapy; Hypnotics and Sedatives; Adult; Randomized Controlled Trials as Topic; Female; Male; Treatment Outcome; Japan; Middle Aged
PubMed: 38925698
DOI: 10.1136/bmjopen-2023-081205 -
International Journal of Pharmaceutics Jun 2024pH-responsive polymeric micelles have been extensively studied for nanomedicine and take advantage of pH differentials in tissues for the delivery of large doses of...
Oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive micelles: Influence of oligo(2-vinyl pyridine)-loading on drug-loading, release and cytotoxicity.
pH-responsive polymeric micelles have been extensively studied for nanomedicine and take advantage of pH differentials in tissues for the delivery of large doses of cytotoxic drugs at specific target sites. Despite significant advances in this area, there is a lack of versatile and adaptable strategies to render micelles pH-responsive that could be widely applied to different payloads and applications. To address this deficiency, we introduce the concept of oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive polymeric micelles as a highly effective approach with broad scope. Herein, we investigate the influence of the oligoelectrolyte, oligo(2-vinyl pyridine) (OVP), loading and polymer molecular weight on the pH-sensitivity, drug loading/release and cytotoxicity of poly(ethylene glycol-b-ε-caprolactone) (PEG-b-PCL) micelles using copolymers with either short or long hydrophobic blocks (PEGPCL and PEGPCL, respectively). The micelles were characterized as a function of pH (7.4 to 3.5). Dynamic light scattering (DLS) revealed narrow particle size distributions (PSDs) for both the blank and OVP-loaded micelles at pH 7.4. While OVP encapsulation resulted in an increase in the hydrodynamic diameter (D) (cf. blank micelles), a decrease in the pH below 6.5 led to a decrease in the D consistent with the ionization and release of OVP and core collapse, which were further supported by proton nuclear magnetic resonance (H NMR) spectroscopy and UV-visible (UV-vis) spectrophotometry. The change in zeta potential (ζ) with pH for the OVP-loaded PEGPCL and PEGPCL micelles was different, suggesting that the location/distribution of OVP in the micelles is influenced by the polymer molecular weight. In general, co-encapsulation of drugs (doxorubicin (DOX), gossypol (GP), paclitaxel (PX) or 7-ethyl-10-hydroxycamptothecin (SN38)) and OVP in the micelles proceeded efficiently with high encapsulation efficiency percentages (EE%). In vitro release studies revealed the rapid, pH-triggered release of drugs from OVP-loaded PEGPCL micelles within hours, with higher OVP loadings providing faster and more complete release. In comparison, no triggered release was observed for the OVP-loaded PEGPCL micelles, implying a strong molecular weight dependency. In metabolic assays the drug- and OVP-loaded PEGPCL micelles were found to result in significant enhancement of the cytotoxicity compared to drug-loaded micelles (no OVP) or other controls. Importantly, micelles with low OVP loadings were found to be nearly as effective as those with high OVP loadings. These results provide key insights into the tunability of the oligoelectrolyte-mediated approach for the effective formulation of pH-responsive micelles and pH-triggered drug release.
PubMed: 38925236
DOI: 10.1016/j.ijpharm.2024.124368 -
Journal of Hazardous Materials Jun 2024Designing an electrode that can generate abundant free radicals and O, which can effectively degrade and detoxify organophosphorus pesticides (OPPs) through a...
Designing an electrode that can generate abundant free radicals and O, which can effectively degrade and detoxify organophosphorus pesticides (OPPs) through a co-oxidation pathway, is important. In this study, we prepared a electrode GO/MoS@AS by supporting MoS on alum sludge (AS) under graphene oxide (GO) nanoconfinement. The results show that the dominant role of O at the cathode and OH at the anode for degradation, in addition to the involvement of O in the cathodic degradation mechanism, can be attributed to the abundant precursor O and HO. Furthermore, calculations using density functional theory and toxicity prediction of products show that the energy (∆E) requirements of OH to break the C-O bond of the pyridine ring and phosphate group are higher than that required for O, and this non-radical oxidation plays a key role in detoxification. In contrast, accelerating ring opening and oxidation processes are attributed to radical oxidation. Above all, the cathodic detoxification is more effective than anodic detoxification. Three prevalent OPPs, chlorpyrifos, glyphosate, and trichlorfon, were degraded in the GO/MoS@AS system by over 90 %, with mineralization rates of 76.66 %, 85.46 %, and 82.18 %, respectively. This study provides insights into the co-oxidation degradation and detoxification mechanism mediated by O and OH.
PubMed: 38925050
DOI: 10.1016/j.jhazmat.2024.135002 -
Journal of Inorganic Biochemistry Jun 2024Halogenation of aliphatic C-H bonds is a chemical transformation performed in nature by mononuclear nonheme iron dependent halogenases. The mechanism involves the...
Halogenation of aliphatic C-H bonds is a chemical transformation performed in nature by mononuclear nonheme iron dependent halogenases. The mechanism involves the formation of an iron(IV)-oxo-chloride species that abstracts the hydrogen atom from the reactive C-H bond to form a carbon-centered radical that selectively reacts with the bound chloride ligand, a process commonly referred to as halide rebound. The factors that determine the halide rebound, as opposed to the reaction with the incipient hydroxide ligand, are not clearly understood and examples of well-defined iron(IV)-oxo-halide compounds competent in C-H halogenation are scarce. In this work we have studied the reactivity of three well-defined iron(IV)-oxo complexes containing variants of the tetradentate 1-(2-pyridylmethyl)-1,4,7-triazacyclononane ligand (Pytacn). Interestingly, these compounds exhibit a change in their chemoselectivity towards the functionalization of C-H bonds under certain conditions: their reaction towards C-H bonds in the presence of a halide anionleads to exclusive oxygenation, while the addition of a superacid results in halogenation. Almost quantitative halogenation of ethylbenzene is observed when using the two systems with more sterically congested ligands and even the chlorination of strong C-H bonds such as those of cyclohexane is performed when a methyl group is present in the sixth position of the pyridine ring of the ligand. Mechanistic studies suggest that both reactions, oxygenation and halogenation, proceed through a common rate determining hydrogen atom transfer step and the presence of the acid dictates the fate of the resulting alkyl radical towards preferential halogenation over oxygenation.
PubMed: 38924872
DOI: 10.1016/j.jinorgbio.2024.112643