Chronic Treatment Research Articles

Chronic opioid pain treatment converted to buprenorphine: A case series using a 3-step low-dose incremental dosing guideline.

We report a 30-case series from the Pain Management Center at the Massachusetts General Hospital where we have applied a guideline to convert chronic treatment for pain from full agonist opioids (FAO) to buprenorphine (BUP). Of the patients, 24 (80 percent) elected to continue BUP over FAO. Five conversions were stopped for side effects (fatigue) and/or lack of sufficient pain reduction. One patient elected not to participate on the day that the conversion was to begin. There were no major adverse events. We conclude that conversion to BUP should be considered as an alternative to treat patients on chronic opioids for pain.

Assessing effects of tamoxifen on tolerance, dependence, and glutamate and glutamine levels in frontal cortex and hippocampus in chronic morphine treatment

Tamoxifen has been shown to reduce glutamate release from presynaptic glutamatergic nerves and reverse tolerance to morphine-induced respiratory depression. Changes in glutamatergic neurotransmission in the central nervous system contribute to morphine tolerance, dependence, and withdrawal. This study, therefore, evaluated effects of tamoxifen on development of analgesic tolerance and dependence, and brain glutamate and glutamine levels in chronic morphine administration. Mice implanted with placebo or morphine pellets were injected with tamoxifen (0.6–2 mg/kg) or vehicle twice daily for 3 days. Nociceptive response was evaluated in the hot plate and tail immersion tests, 4, 48 and 72 h post-implant, and following a challenge dose of morphine (10 mg/kg). Withdrawal signs were determined after naloxone (1 mg/kg) administration. Morphine increased nociceptive threshold which declined over time. At 72 h, acute morphine elicited tolerance to the analgesic effect in the hot plate test in vehicle or tamoxifen administered animals. In the tail immersion test, however, tolerance to morphine analgesia was observed in tamoxifen, but not vehicle, co-administration. Tamoxifen did not reduce withdrawal signs. In contrast to previous reports, glutamate and glutamine levels in the hippocampus and frontal cortex did not change in the morphine-vehicle group. Confirming previous findings, tamoxifen (2 mg/kg) decreased glutamate and glutamine concentrations in the hippocampus in animals with placebo pellets. Both doses of tamoxifen significantly changed glutamate and/or glutamine concentrations in both regions in morphine pellet implanted animals. These results suggest that tamoxifen has no effect on dependence but may facilitate tolerance development to the antinociception, possibly mediated at the spinal level, in chronic morphine administration.

Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) via regulating the synaptic plasticity in hippocampus

TSPO, translocator protein (18 kDa) ligands have demonstrated consistent antidepression and anxiolytic effects in several preclinical studies. This study aimed to examine whether YL-IPA08[N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-ichlorophenyl) -7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, could alleviate anxiety-related behaviors induced by electric shock (ES) and investigate its underlying mechanism. As expected, we showed that chronic treatment with YL-IPA08 significantly reversed anxiety-related behaviors induced by electrical stimulation (0.5 mA, 12 times, duration 1s, interval 10s) exposure. Using the analysis of RNA-sequencing (RNA-seq) technology, it was found that the differential genes associated with the anxiolytic effect of YL-IPA08 were mainly related to synaptic plasticity. Furthermore, YL-IPA08 restored the decreased levels of brain-derived neurotrophic factor (BDNF), synapse-related protein (e.g. synapsin-1 and post-synaptic density95, PSD95), and the number of doublecortin (DCX) + neurons in the hippocampus of post-ES mice. In addition, YL-IPA08 also enhanced the dendritic complexity and dendritic spine density of hippocampal dentate gyrus (DG) granule neurons. Meanwhile, the induction of long-term potentiation (LTP) was significantly enhanced by YL-IPA08. In summary, the findings from the current study showed that YL-IPA08 exerted a clear anxiolytic effect, which might be partially mediated by promoting hippocampal neuroplasticity.

Glucocorticoid-induced osteoporosis is prevented by dietary prune in female mice.

Glucocorticoid-induced osteoporosis (GIO) is a significant side effect of prolonged glucocorticoid (GC) treatment. Chronic GC treatment also leads to trabecular bone loss and gut microbiota dysbiosis in mice. The gut dysbiosis is mechanistically linked to GIO, which indicates that the microbiota can be targeted to prevent GIO. Prunes, a dried fruit and prebiotic, have emerged in the literature as an effective treatment for sex-steroid deficiency induced osteoporosis (primary osteoporosis). Prunes also significantly alter the composition of the gut microbiota in both rodent models and human studies. Therefore, we tested if dietary prune (DP) supplementation could prevent GC-induced bone loss and affect microbiota composition in an established model of GIO. Sixteen-week-old, skeletally mature, female C57BL/6J mice were treated with a subcutaneous 5mg placebo or prednisolone pellet for 8weeks and fed an AIN-93M control diet or a diet modified to include 5, 15, or 25% (w/w) dried California prune powder. As expected, GC treated mice developed significant trabecular bone loss in the distal femur. More importantly, as little as 5% DP supplementation effectively prevented trabecular bone loss. Further, dose dependent increases in trabecular bone volume fraction were observed in GC + 15% and GC + 25% DP mice. Amazingly, in the placebo (non-GC treated) groups, 25% DP supplementation caused a ∼3-fold increase in distal femur trabecular bone volume fraction; this sizable bone response has not been previously observed in healthy mice with gut targeted natural treatments. Along with the striking effect on bone health, GC treatment and 25% DP supplementation led to drastic shifts in gut microbiota composition and several specific changes are strongly associated with bone health. Taken together, these results are the first to demonstrate that DP supplementation effectively prevents the negative effects of prolonged GC therapy on trabecular bone health and strongly associates with shifts in the composition of the gut microbiota.

(375) Assessing Infertility Literacy and Knowledge Gaps Amongst Patients with Cystic Fibrosis

Abstract Introduction As patients with cystic fibrosis live longer into their reproductive years, fertility concerns are rising. We hypothesized that while patients with CF may be informed of the impact of their disease on their reproductive potential, they remain unaware of the promising role of assisted reproductive technology (ART) in helping them conceive biological children. Objective Employ a cross-sectional survey to understand experiences, preferences, and current concerns in the CF community around infertility education and infertility healthcare access. Methods This study was reviewed and approved as exempt status by the Institutional Review Board (IRB) exemption as non-human research. We distributed a voluntary and anonymous Qualtrics survey to CF patients and CF advocacy organizations to assess patient understanding of infertility within CF. The survey consisted of 21 questions and aimed to capture demographics, reproductive education specific to CF, preferences on infertility education, current conception practices, and any infertility treatment. Preference questions were assessed using the Likert Scale, and personal experiences questions were answered through free text. Results Forty-one respondents completed the survey (median age of 36 ± 14 years). The median age reported for learning about CF-associated infertility was 18 years. Respondents preferred that reproductive and infertility education be provided early; 43% reported the optimal age of education was younger than 18 years while 50% reported between 18-24 years. Of the respondents trying to conceive, 43% of patients have been trying to conceive for 1-3 years qualifying for infertility. Yet, the majority of those patients (69%) have not been offered semen analysis and 90% have not had previous fertility treatments. Conclusions Patients with CF are highly educated and empowered regarding the chronic treatment of their disease. Historically, issues regarding infertility and conception have been cast to the side, given the severity of other issues, such as lung function and survival. As CF patients live longer and healthier lives, they seek healthcare in other facets, including reproduction and infertility. The findings in our study highlight the importance of discussing reproduction and its limitation in CF at a young age to preemptively empower and prepare patients and their future partners. Furthermore, our study demonstrates a strong need to strengthen the communication between CF care teams and fertility specialists. Both men and women with CF would benefit from receiving respective guidance from embryologists and andrologists to maximize their chances of conception. Disclosure Yes, this is sponsored by industry/sponsor: Cystic Fibrosis Foundation. Clarification: No industry support in study design or execution.

Early chronic fasudil treatment rescues hippocampal alterations in the Ts65Dn model for down syndrome

Down syndrome (DS) is the most common genetic disorder associated with intellectual disability. To study this syndrome, several mouse models have been developed. Among the most common is the Ts65Dn model, which mimics most of the alterations observed in DS. Ts65Dn mice, as humans with DS, show defects in the structure, density, and distribution of dendritic spines in the cerebral cortex and hippocampus. Fasudil is a potent inhibitor of the RhoA kinase pathway, which is involved in the formation and stabilization of dendritic spines. Our study analysed the effect of early chronic fasudil treatment on the alterations observed in the hippocampus of the Ts65Dn model. We observed that treating Ts65Dn mice with fasudil induced an increase in neural plasticity in the hippocampus: there was an increment in the expression of PSA-NCAM and BDNF, in the dendritic branching and spine density of granule neurons, as well as in cell proliferation and neurogenesis in the subgranular zone. Finally, the treatment reduced the unbalance between excitation and inhibition present in this model. Overall, early chronic treatment with fasudil increases cell plasticity and eliminates differences with euploid animals.

Chronic Treatment with Nigella sativa Oil Exerts Antimanic Properties and Reduces Brain Inflammation in Rats.

Nigella sativa (NS) is a native herb consumed habitually in several countries worldwide, possessing manifold therapeutic properties. Among them, anti-inflammatory features have been reported, presumably relating to mechanisms involved in the nuclear factor kappa-B pathway, among others. Given the observed association between neuroimmune factors and mental illness, the primary aim of the present study was to examine the effects of chronic NS use on manic-like behavior in rats, as well as analyze levels of brain inflammatory mediators following NS intake. Using male and female rats, baseline tests were performed; thereafter, rats were fed either regular food (control) or NS-containing food (treatment) for four weeks. Following intervention, behavioral tests were induced (an open field test, sucrose consumption test, three-chamber sociality test, and amphetamine-induced hyperactivity test). Subsequently, brain samples were extracted, and inflammatory mediators were evaluated, including interleukin-6, leukotriene B4, prostaglandin E2, tumor necrosis factor-α, and nuclear phosphorylated-p65. Our findings show NS to result in a marked antimanic-like effect, in tandem with a positive modulation of select inflammatory mediators among male and female rats. The findings reinforce the proposed therapeutic advantages relating to NS ingestion.

Chronic Treatment with Serotonin Selective Reuptake Inhibitors Does Not Affect Regrowth of Serotonin Axons Following Amphetamine Injury in the Mouse Forebrain.

A current hypothesis to explain the limited recovery following brain and spinal cord trauma stems from the dogma that neurons in the mammalian central nervous system lack the ability to regenerate their axons after injury. Serotonin (5-HT) neurons in the adult brain are a notable exception in that they can slowly regrow their axons following chemical or mechanical lesions. This process of regrowth occurs without intervention over several months and results in anatomical recovery that approximates the preinjured state. During development, serotonin is a trophic factor, playing a role in both cell survival and axon growth. Additionally, some studies have shown that stroke patients treated after injury with serotonin selective reuptake inhibitors (SSRIs) appeared to have improved recovery. To test the hypothesis that serotonin can influence the regrowth of 5-HT axons, mice received a high dose of para-chloroamphetamine (PCA) to induce widespread retrograde degeneration of 5-HT axons. Then, after a short rest period to avoid any interaction with the acute injury phase, SSRIs were administered daily for 6 or 10 weeks. Using immunohistochemistry in 5-HT transporter-GFP BAC transgenic mice, we determined that while PCA led to a rapid initial decrease in total 5-HT axon length in the somatosensory cortex, visual cortex, or area CA1 of the hippocampus, treatment with either fluoxetine or sertraline (two different SSRIs) did not affect the recovery of axon length. These results suggest that chronic SSRI treatment does not affect the regrowth of 5-HT axons and argue against SSRIs as a potential therapy following brain injury.

A global perspective on stepping down chronic spontaneous urticaria treatment: Results of the Urticaria Centers of Reference and Excellence SDown-CSU study.

Although there have been significant advances in the treatment of chronic spontaneous urticaria (CSU) in recent years, there remains a lack of clear guidance on when and how to step down treatment in responders. This study aims to investigate stepping down approaches of different steps of CSU treatment from a global perspective. "Stepping down chronic spontaneous urticaria treatment" (SDown-CSU) is an international, multicenter, observational, cross-sectional, survey-based study of the Urticaria Centers of Reference and Excellence (UCARE) network. The questionnaire included 48 questions completed by physicians in the UCARE network. Surveys completed by 103 physicians from 81 UCAREs and 34 countries were analyzed. Seventy-eight percent of the participants responded that they had a national urticaria management guideline written by their professional societies and 28% responded that they had to operate under a regulatory guideline proposed by central health funding organizations. Seventy-two and 58.7% of these national recommendations do not contain any detailed information on when and/or how CSU treatment should be discontinued. There was a lack of detailed information on antihistamines and cyclosporine in particular. A predefined maximum duration was generally not applicable to omalizumab and cyclosporine (81% and 82%, respectively). Nearly all UCAREs step down omalizumab within 6months from the first controlled status and 42% discontinue cyclosporine after 6months regardless of the control status. The findings from the SDown-CSU study clearly highlight a global need for guidance on the process of stepping down treatment in CSU. Additionally, the study offers a step-down algorithm applicable to all stages of CSU treatment.

Chronic but not acute nicotine treatment ameliorates acute inflammation-induced working memory impairment by increasing CRTC1 and HCN2 in adult male mice.

Systemic inflammation in which lipopolysaccharide (LPS) is released into circulation can cause cognitive dysfunction and we have previously shown that LPS impaired working memory (WM) which refers to the ability to guide incoming behavior by retrieving recently acquired information. However, the mechanism is not very clear, and currently, there is no approved strategy to improve inflammation-induced WM deficit. Notably, epidemiological studies have demonstrated a lower occurrence rate of inflammatory-related diseases in smoking patients, suggesting that inflammation-induced WM impairment may be improved by nicotine treatment. Here, our object is to investigate the effect and potential mechanisms of acute and chronic nicotine treatment on LPS-produced WM deficiency. Delayed alternation T-maze task (DAT) was applied for evaluating WM which includes both the short-term information storage and the ability to correct errors in adult male mice. Immunofluorescence staining and immunoblotting were used for assessing the levels and distribution of CREB-regulated transcription coactivator 1 (CRTC1) and hyperpolarization-activated cation channels 2 (HCN2) in the medial prefrontal cortex (mPFC) and hippocampus. Quantitative PCR and ELISA were employed for analyzing the mRNA and protein levels of TNF-α and IL-1β. Our results revealed that administration of LPS (i.p.) at a dose of 0.5 mg/kg significantly produced WM impairment in the DAT task accompanied by an increase in IL-1β and TNF-α expression in the mPFC. Moreover, intra-mPFC infusion of IL-1Ra, an IL-1 antagonist, markedly alleviated LPS-induced WM deficiency. More important, chronic (2 weeks) but not acute nicotine (0.2 mg/kg, subcutaneous) treatment significantly alleviated LPS-induced WM deficiency by upregulating CRTC1 and HCN2. Of note, intra-mPFC infusion of HCN blocker ZD7288 produced significant WM deficiency. In summary, in this study, we show that chronic nicotine treatment ameliorates acute inflammation-induced working memory deficiency by increasing CRTC1 and HCN2 in adult male mice.

Enhanced Oral Bioavailability of Progesterone in Bilosome Formulation: Fabrication, Statistical Optimization, and Pharmacokinetic Study.

Progesterone, a female sex steroid hormone, is highly lipophilic, leading to poor oral bioavailability. This study aimed to develop a progesterone bilosome system to enhance its oral bioavailability and retain it longer in the body. Progesterone vesicles were formulated with bile salts by thin film hydration method to prevent enzymatic and bile acid degradation. The Box-Behnken experimental design was used to statistically optimize progesterone bilosomes by checking the effect of phosphatidylcholine, cholesterol, and sodium deoxycholate on vesicle size, zeta potential, and entrapment efficiency. The optimum batch showed 239.5nm vesicle size, -28.2mV zeta potential and 84.08% entrapment efficiency, respectively, which were significantly affected by phosphatidylcholine and cholesterol concentration. The successful incorporation of progesterone in the system was evident from ATR-FTIR analysis that revealed no sharp progesterone peaks in bilosomes. TEM analysis confirmed the spherical structure and uniform bilosome vesicles. Furthermore, the in vitro drug release of progesterone bilosomes revealed a sustained pattern exhibiting 90% drug release in 48h. The pharmacokinetic study in female ovariectomized Wistar rats confirmed the 4.287- and 9.75-fold enhanced oral bioavailability of the progesterone bilosomes than marketed capsules and progesterone API, respectively. Therefore, progesterone bilosome formulation can be further explored for improved oral administration in chronic treatments.

Abstract WP295: Blocking the VCAM1-VLA4 Axis Prevents Cognitive Decline in a Mouse Model of Infarct-Induced Neurodegeneration

Introduction: Infarct-induced neurodegeneration occurs chronically after stroke and can be prevented by inhibiting B cell influx. Vascular cell adhesion molecule 1 (VCAM1) facilitates immune cell diapedesis by binding very late antigen 4 (VLA4), and plasma levels are elevated after stroke in humans and mice. We hypothesized that chronic treatment with antibodies anti-VCAM1 or anti-VLA4 would reduce lymphocyte infiltration and prevent cognitive decline. Methods: Aged (10 month old) C57BL/6 male & female mice (N=9-10/group) underwent permanent middle cerebral artery occlusion and were dosed with anti-VCAM1, anti-VLA4, or control IgG every 3 days beginning 4 days after stroke for 10 weeks. Sham mice were also dosed with IgG. Barnes maze and Novel object were performed at -1, 1 and 6 weeks and single-cell RNA sequencing was performed on immune and endothelial cells at 10 weeks. Results: Blocking either VCAM1 or VLA4 reduced B cells 67% or 55%, respectively, compared to IgG treated stroked mice. Stroked mice treated with IgG developed a cognitive deficit in both Barnes maze and novel object by 6 weeks, while both anti-VCAM1 and anti-VLA4 treated mice performed comparably to sham animals in the Barnes maze (p=0.398; p=0.972, respectively). Similarly, sham IgG (p<0.0001), stroke anti-VCAM1 (p<0.0001) and VLA4 (p=0.0059) could all perform the novel object task. Single-cell sequencing of immune and brain endothelial cells demonstrated that most transcriptional changes occur in endothelial cells and not immune cells, and that anti-VCAM1 and anti-VLA4 induce similar transcriptional changes compared to control IgG after stroke. Specifically, both therapeutic antibodies restore heat shock protein expression ( Dnaja1, Hsp90ab1, Hspa8 ) and decrease inflammatory genes CD74 and IL1r1 . Transcriptional changes also reflect increased translation and Sox18 upregulation, consistent with angiogenesis. Conclusion: Blocking either VCAM1 or VLA4 prevents infarct-induced neurodegeneration in aged mice. Changes in endothelial cell transcription and decreased immune cells in the brain may both contribute to therapeutic effects. Together, these findings establish the VCAM1-VLA4 axis as a promising target to prevent infarct-induced neurodegeneration.

Determinants of Health Behavior for Effective Treatment and Prevention of Chronic Obstructive Pulmonary Disease: Empirical Advances

Objective: The prime objective of this research is to investigate the impact of health behavior, quitting smoking, access to healthcare, and patients' adherence to healthcare on chronic obstructive pulmonary disease treatment. Methods: A 7-point Likert scale questionnaire was administered to collect the data. A sample size of 471 respondents was used for the determination of results with a structural equation modeling approach. Smart PLS 4 was used for testing the results of the measurement model assessment and structural model assessment. Results: The findings of the current study showed that health behavior, quitting smoking, access to healthcare, and patients' adherence to healthcare are significant antecedents of chronic obstructive pulmonary disease effective treatment. Conclusion: This research reported that the emphasis and support for health behavior improvement, quitting smoking support, access to better healthcare, and patient adherence to healthcare are opportunities useful for chronic obstructive pulmonary disease effective treatment all over the world. The research has reliable theoretical as well as practical implications that are critical to improving the body of knowledge and practices for the improvements in the treatment of chronic obstructive pulmonary disease.

Anemia in chronic kidney disease

Anemia associated with chronic kidney disease is a common complication and a cause of increased morbidity and mortality. Hemoglobin levels should be closely monitored in all stages of chronic kidney disease. In this review, current clinical practice for anemia associated with chronic kidney disease, including pathophysiology, diagnosis, and treatment management, is reviewed.

Chronic cortisol stimulation enhances hypothalamus-specific enrichment of metabolites in the rainbow trout brain.

The hypothalamus is a key integrating center that is involved in the initiation of the corticosteroid stress response, and in regulating nutrient homeostasis. Although cortisol, the principal glucocorticoid in humans and teleosts, plays a central role in feeding regulation, the mechanisms are far from clear. We tested the hypothesis that the metabolic changes to cortisol exposure signal an energy excess in the hypothalamus, leading to feeding suppression during stress in fish. Rainbow trout (Oncorhynchus mykiss) were administered a slow-release cortisol implant for 3 days, and the metabolite profiles in the plasma, hypothalamus, and the rest of the brain were assessed. Also, U-13C-glucose was injected into the hypothalamus by intracerebroventricular (ICV) route, and the metabolic fate of this energy substrate was followed in the brain regions by metabolomics. Chronic cortisol treatment reduced feed intake, and this corresponded with a downregulation of the orexigenic gene agrp, and an upregulation of the anorexigenic gene cart in the hypothalamus. The U-13C-glucose-mediated metabolite profiling indicated an enhancement of glycolytic flux and tricarboxylic acid intermediates in the rest of the brain compared with the hypothalamus. There was no effect of cortisol treatment on the phosphorylation status of AMPK or mechanistic target of rapamycin in the brain, whereas several endogenous metabolites, including leucine, citrate, and lactate were enriched in the hypothalamus, suggesting a tissue-specific metabolic shift in response to cortisol stimulation. Altogether, our results suggest that the hypothalamus-specific enrichment of leucine and the metabolic fate of this amino acid, including the generation of lipid intermediates, contribute to cortisol-mediated feeding suppression in fish.NEW & NOTEWORTHY Elevated cortisol levels during stress suppress feed intake in animals. We tested whether the feed suppression is associated with cortisol-mediated alteration in hypothalamus metabolism. The brain metabolome revealed a hypothalamus-specific metabolite profile suggesting nutrient excess. Specifically, we noted the enrichment of leucine and citrate in the hypothalamus, and the upregulation of pathways involved in leucine metabolism and fatty acid synthesis. This cortisol-mediated energy substrate repartitioning may modulate the feeding/satiety centers leading to the feeding suppression.

Successful wound healing by autologous peripheral blood mononuclear cell therapy in a diabetic patient on hemodialysis with no-option critical limb ischemia: a case report.

Peripheral artery disease is a common condition in patients on chronic dialysis treatment, end-stage kidney failure itself being a risk factor. The most severe stage of peripheral artery disease, critical limb ischemia, causes marked chronic pain and is associated with risk of limb loss. Despite improvements in revascularization procedures, the results of limb salvage proceduresamong dialysis patients remains poor, and lower extremity amputation is associated with high mortality and grimsocio-economic implications. We report on alimb salvage approach that was successfully employed in a 74-year-old woman on hemodialysis suffering from no-option critical limb ischemia complicated by diabetic foot infection, i.e. otherwise a candidate for major amputation. The approach consists in implanting in the wound bed of the affected limb a concentrate of autologous peripheral blood mononuclear cells collected from the peripheral blood of the patient using a selective filtration separation system. The procedure, performed by a vascular surgeon in an outpatient setting and sterile conditions, was repeated three times at intervals of 15days, and was well tolerated; no adverse safety signals were observed. Complete wound healing was obtained, with successful limb rescue.

Sericin Improves Memory Impairment Via Activation of the PKA-CREB-BDNF Signaling Pathway and Suppression of Oxidative Stress in Ovariectomized Mice.

Menopause results in estrogen hormone deficiency which causes changes in brain morphology and cognitive impairments. The risk of breast and ovarian cancer increases with estrogen therapy. Thus, finding a substitute treatment option for women in menopause is necessary. In the current study, the impact of chronic sericin treatment (200mg/kg/day for 6weeks, gavage) on memory process, oxidative stress markers, synaptic neurotransmission, and acetylcholinesterase (AChE) activity in the hippocampus (HIP) of ovariectomized (OVX) mice was examined and compared to the effects of 17β-estradiol (Es; 20µg/kg, s.c.). The results demonstrated that sericin and Es administration improved spatial and recognition memory of the OVX animals in the both Lashley III maze and novel object recognition tests. Moreover, sericin-treated OVX mice showed decreased ROS levels, increased endogenous antioxidant defense capacity, and decreased AChE activity in the HIP. Additionally, sericin and Es therapy up-regulated pre-and-post-synaptic protein markers and increased BDNF, CREB, and protein kinase A (PKA) protein expressions in the HIP of OVX mice. Overall, the activation of the PKA-CREB-BDNF signaling pathway by sericin can provide protection against OVX-induced cognitive dysfunction, making it a potential alternative for managing cognitive deficits in postmenopausal women.

In-sewer stability assessment of 140 pharmaceuticals, personal care products, pesticides and their metabolites: Implications for wastewater-based epidemiology biomarker screening

The monitoring of pharmaceuticals, personal care products (PCPs), pesticides, and their metabolites through wastewater-based epidemiology (WBE) provides timely information on pharmaceutical consumption patterns, chronic disease treatment rates, antibiotic usage, and exposure to harmful chemicals. However, before applying them for quantitative WBE back-estimation, it is necessary to understand their stability in the sewer system to screen suitable WBE biomarkers thereby reducing research uncertainty. This study investigated the in-sewer stability of 140 typical pharmaceuticals, PCPs, pesticides, and their metabolites across 15 subcategories, using a series of laboratory sewer sediment and biofilm reactors. For the first time, stability results for 89 of these compounds were reported. Among the 140 target compounds, 61 biomarkers demonstrated high stability in all sewer reactors, while 41 biomarkers were significantly removed merely by sediment processes. For biomarkers exhibiting notable attenuation, the influence of sediment processes was generally more pronounced than biofilm, due to its stronger microbial activities and more pronounced diffusion or adsorption processes. Adsorption emerged as the predominant factor causing biomarker removal compared to biodegradation and diffusion. Significantly different organic carbon–water partitioning coefficient (Koc) and distribution coefficient at pH = 7 (logD) values were observed between highly stable and unstable biomarkers, with most hydrophobic substances (Koc > 100 or logD > 2) displaying instability. In light of these findings, we introduced a primary biomarker screening process to efficiently exclude inappropriate candidates, achieving a commendable 77 % accuracy. Overall, this study represents the first comprehensive report on the in-sewer stability of 89 pharmaceuticals, PCPs, pesticides, and their metabolites, and provided crucial reference points for understanding the intricate sewer sediment processes.

Chronic Morphine Treatment and Antiretroviral Therapy Exacerbate HIV-Distal Sensory Peripheral Neuropathy and Induce Distinct Microbial Alterations in the HIV Tg26 Mouse Model.

Distal Sensory Peripheral Neuropathy (DSP) is a common complication in HIV-infected individuals, leading to chronic pain and reduced quality of life. Even with antiretroviral therapy (ART), DSP persists, often prompting the use of opioid analgesics, which can paradoxically worsen symptoms through opioid-induced microbial dysbiosis. This study employs the HIV Tg26 mouse model to investigate HIV-DSP development and assess gut microbiome changes in response to chronic morphine treatment and ART using 16S rRNA sequencing. Our results reveal that chronic morphine and ART exacerbate HIV-DSP in Tg26 mice, primarily through mechanical pain pathways. As the gut microbiome may be involved in chronic pain persistence, microbiome analysis indicated distinct bacterial community changes between WT and Tg26 mice as well as morphine- and ART-induced microbial changes in the Tg26 mice. This study reveals the Tg26 mouse model to be a relevant system that can help elucidate the pathogenic mechanisms of the opioid- and ART-induced exacerbation of HIV-associated pain. Our results shed light on the intricate interplay between HIV infection, ART, opioid use, and the gut microbiome in chronic pain development. They hold implications for understanding the mechanisms underlying HIV-associated pain and microbial dysbiosis, with potential for future research focused on prevention and treatment strategies.

Chronic exposure to imipramine induces a switch from depression-like to mania-like behavior in female serotonin transporter knockout rats: Role of BDNF signaling in the infralimbic cortex

BackgroundBipolar disorder (BD) is a highly burdensome psychiatric disorder characterized by alternating states of mania and depression. A major challenge in the clinic is the switch from depression to mania, which is often observed in female BD patients during antidepressant treatment such as imipramine. However, the underlying neural basis is unclear. MethodsTo investigate the potential neuronal pathways, serotonin transporter knockout (SERT KO) rats, an experimental model of female BD patients, were subjected to a battery of behavioral tests under chronic treatment of the antidepressant imipramine. In addition, the expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling was examined in the prefrontal cortex. ResultsChronic exposure to imipramine reduced anxiety and sociability and problem-solving capacity, and increased thigmotaxis and day/night activity in all animals, but specifically in female SERT KO rats, compared to female wild-type (WT) rats. Further, we found an activation of BDNF-TrkB-Akt pathway signaling in the infralimbic, but not prelimbic, cortex after chronic imipramine treatment in SERT KO, but not WT, rats. LimitationsRepeated testing behaviors could potentially affect the results. Additionally, the imipramine induced changes in behavior and in the BDNF system were measured in separate animals. ConclusionsOur study indicates that female SERT KO rats, which mirror the female BD patients with the 5-HTTLPR s-allele, are at higher risk of a switch to mania-like behaviors under imipramine treatment. Activation of the BDNF-TrkB-Akt pathway in the infralimbic cortex might contribute to this phenotype, but causal evidence remains to be provided.