Chronic Treatment Research Articles

Nuclear factor erythroid 2-related factor 2 activation in streptozotocin-induced diabetic rats normalize renal hemodynamics and oxygen consumption

Background: Diabetic kidney disease is a major contributor to end stage renal disease. A change in kidney oxygen homeostasis leading to decreased tissue oxygen tension is an important factor initiating alterations in kidney function in diabetes. However, the mechanism contributing to changed oxygen homeostasis is still unclear. Hyperglycemia-induced production of reactive oxygen species and an altered response to them have previously been demonstrated. In the present study, chronic treatment with DL-sulforaphane to induce nuclear factor erythroid 2-related factor 2 (Nrf2) expression, a master transcriptional regulator binding to antioxidant response elements inducing increased protection against reactive oxygen species, is studied. Methods: Sprague–Dawley rats were made diabetic using streptozotocin and either left untreated or received daily subcutaneous injections of DL-sulforaphane for 4 weeks. Age-matched non-diabetic rats served as controls. After 4 weeks of treatment, rats were anesthetized using thiobutabarbital, and kidney functions were studied in terms of glomerular filtration rate (GFR), renal blood flow (RBF), sodium transport, kidney oxygen consumption, and kidney oxygen tension. Mitochondria was isolated from kidney cortical tissue and investigated using high-resolution respirometry. Results: GFR was increased in diabetics but not RBF resulting in increased filtration fraction in diabetics. DL-sulforaphane treatment did not affect RBF and GFR in controls but decreased the same parameters in diabetics. Increased GFR resulted in increased sodium transport and oxygen consumption, hence decreased efficiency in diabetics compared to controls. Increased oxygen consumption in diabetics resulted in decreased cortical tissue oxygen tension. DL-sulforaphane treatment decreased oxygen consumption in diabetics, whereas transport efficiency was not significantly affected. DL-sulforaphane treatment increased cortical pO2 in diabetics. Conclusions: DL-sulforaphane treatment affects renal hemodynamics, improving cortical oxygen tension but not mitochondrial efficiency.

Palmoplantar pustulosis successfully treated with topical roflumilast 0.3%

Palmoplantar pustulosis is a difficult-to-treat, immune-mediated skin disease that presents as sterile pustules on the palms and soles. While thought to be related to psoriasis vulgaris, precise biologics that target the same cytokines as psoriasis vulgaris have led to inadequate and difficult treatment. Topical corticosteroids have a broader anti-inflammatory profile compared with biologics but are limited by adverse events making chronic treatment unsuitable. We report the case of an 82-year-old patient who was successfully treated with topical roflumilast 0.3% once daily for the treatment of palmoplantar pustulosis that was refractory to topical corticosteroid use.

Diagnosis and Treatment of Presumed Naltrexone-XR-precipitated Opioid Withdrawal in a Patient Chronically Treated With Buprenorphine-XR: A Case Report.

Naltrexone, buprenorphine, and methadone are Food and Drug Administration-approved medications for the treatment of opioid use disorder in the United States. Naltrexone, an opioid antagonist, can precipitate opioid withdrawal if administered too quickly after the use of full or partial opioid agonists for those with either dependence or use disorder. We describe a case of severe precipitated opioid withdrawal syndrome after reported buprenorphine extended-release (XR) administration, despite the patient having been stable on buprenorphine-XR for several years, with no missed doses or recent opioid use. Naltrexone levels were sent and helped to diagnose suspected inadvertent naltrexone-XR administration in this patient, which was likely the etiology of his precipitated opioid withdrawal syndrome. We suggest the use of high-dose buprenorphine, as well as adjunctive medications including benzodiazepines, as a treatment strategy for naltrexone-XR precipitated withdrawal in the setting of chronic buprenorphine-XR treatment.

Smart Dressings and Their Applications in Chronic Wound Management.

During chronic wound healing, the inflammatory phase can endure for extended periods, heavily impeding or halting the process. Regular inspections and dressing changes are crucial. Modern dressings like hydrogels, hydrocolloids, and foam provide protection and an optimal healing environment. However, they have limitations in offering real-time wound bed status and healing rate. Evaluation relies heavily on direct observation, and passive dressings fail to identify subtle healing differences, preventing adaptive adjustments in biological factors and drug concentrations. In recent years, the clinical field recognizes the value of integrating intelligent diagnostic tools into wound dressings. By monitoring biomarkers linked to chronic wounds' inflammatory state, real-time data can be captured, reducing medical interventions and enabling more effective treatment plans. This fosters innovation in chronic wound care. Researchers have developed smart dressings with sensing, active drug delivery, and self-adjustment capabilities. These dressings detect inflammatory markers like temperature, pH, and oxygen content, enhancing drug bioavailability on the wound surface. As wound healing technology evolves, these smart dressings hold immense potential in chronic wound care and treatment. This comprehensive review updates our understanding on the role and mechanism of action of the smart dressings in chronic refractory wounds by summarizing and discussing the latest research progresses, including the intelligent monitoring of wound oxygen content, temperature, humidity, pH, infection, and enzyme kinetics; intelligent drug delivery triggered by temperature, pH, near-infrared, and electricity; as well as the intelligent self-adjustment of pressure and shape. The review also delves into the constraints and future perspectives of smart dressings in clinical settings, thereby advancing the development of smart wound dressings for chronic wound healing and their practical application in clinical practice.

Physiologically-Based Pharmacokinetic Modeling and In Vitro–In Vivo Correlation of TV-46000 (Risperidone LAI): Prediction from Dog to Human

The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in adults. Following sc injection, the copolymers together with risperidone precipitate to form a sc depot under the skin to deliver therapeutic levels of risperidone over a prolonged period of either 1 month or 2 months, depending upon the dose. This work presents the strategy and the results of the physiologically-based pharmacokinetic (PBPK) modeling and establishing of in vitro–in vivo correlation (IVIVC) for the prediction of TV-46000 pharmacokinetic profile in humans, using in vitro release, intravenous (iv), and sc single-dose pharmacokinetic data in beagle dogs. The resulting simulated TV-46000 PK profile in humans showed that the shape of the predicted risperidone and its active metabolite 9-OH-risperidone PK profiles was different from the observed one, thus suggesting that the TV-46000 release profile was species-dependent and cannot be directly extrapolated from dog to human. In conclusion, while level A IVIVC cannot be claimed, this work combining PBPK and IVIVC modeling represents an interesting alternative approach for complex injectable formulations where classical methods are not applicable.

P-291 In women with endometriosis, effective treatment of chronic endometritis with antibiotics lowers serum CA-125 levels

Abstract Study question To evaluate the effect of chronic endometritis treatment on serum CA-125 levels in women with endometriosis. Summary answer Cure of chronic endometritis leads to a reduction in serum Ca-125 levels in women with endometriosis. What is known already Endometriosis is a chronic inflammatory disease characterized by the ectopic growth of endometrial tissue outside the uterine cavity. It is hypothesized that the disease exerts direct inflammatory effects on the ovaries, fallopian tubes, and the eutopic endometrium. In endometriosis, CA-125 levels are often elevated. Literature reports a frequent coexistence of endometriosis and chronic endometritis (CE) in women undergoing hysterectomy for benign indications. CE, characterized by macroscopic and histological alterations of the endometrium, was present in 38.5%-42.3% of women with endometriosis, compared to lower prevalence rates in controls infertile patients without endometriosis, supporting a potential etiopathogenic link between endometriosis and CE. Study design, size, duration This retrospective case-control study was conducted at the Department of Obstetrics and Gynecology, University of Bari. The study included 51 patients suffering of both ovarian endometriosis and CE. The primary objective was to investigate whether CE cure modifies serum CA-125 levels among women with ovarian endometriosis. The secondary objective was to assess any modifications in the size of endometriotic cysts following the cure of CE. Recruitment period was from September 2021 to February 2023. Participants/materials, setting, methods All patients received antibiotic therapy (100 mg of doxycycline, twice daily for ten days) and, the following month, hysteroscopy with control biopsy. Of these, 36 women were cured of chronic endometritis (Group A), while 15 women showed persistent disease (Group B). Endometriosis was diagnosed by transvaginal ultrasound and chronic endometritis through hysteroscopy, histology, and immunohistochemistry for CD138. Serum CA-125 levels were measured before antibiotic therapy and approximately 3 months later. Main results and the role of chance The primary outcome was to compare the change in CA-125 values between women cured of chronic endometritis and women with persistent disease. There were no statistically significant differences in baseline characteristics between the groups (p=ns). The majority of patients in both groups had a single ovarian endometrioma and the micropolypoid endometrial appearance was the predominant finding of chronic endometritis observed during hysteroscopy in both Groups. In Group A, the mean CA-125 value significantly decreased after antibiotic therapy from 58.56 U/mL (± 32.45) to 38.25 U/mL (± 17.31) (p < 0.001). No significant changes in CA-125 values were observed in Group B before and after antibiotic therapy (69.70 ± 27.42 versus 67.47 ± 24.52 U/mL, p=ns). The absolute change in CA-125 values was significantly greater in terms of reduction in Group A compared to Group B (-20.31 ± 27.09 versus -2.13 ± 12.51 U/mL; p = 0.02). Adjustment for confounders in a multivariable regression model revealed that the cure of chronic endometritis was independently associated with a significant decrease in absolute serum CA-125 levels (p = 0.006). Cyst size did not significantly change after antibiotic therapy in both groups (p=ns). Limitations, reasons for caution The main weakness of our study is that CA-125 was only measured once before and once after treatment of CE with a course of antibiotics. Moreover, our study does not allow for inferences regarding the impact of the observed reduction in serum CA-125 on the subjective symptoms related to endometriosis. Wider implications of the findings Our study constitutes the first demonstration that effective treatment of CE results in a significant decrease in a non-invasive marker of endometriosis, CA-125 supporting the emerging concept that the endometriosis might have an infectious origin. Trial registration number not applicable

Antiepileptic Drugs as Prophylaxis for Seizures after Excision of Brain Tumors

Abstract Background Seizures are the most common & most serious side effect of cranial surgery. The latter condition requires chronic treatment with Antiepileptic drugs (AEDs) and comes with relevant socioeconomic sequelae. The routine prophylactic use of AEDs for people undergoing tumor resection has remained controversial due to the risk of postoperative seizures. Some Neurosurgeons are advocates to the use of AEDs to reduce the risk of these seizures. Objective To evaluate the efficacy of prophylactic AEDs routinely in brain tumor patients without previous history of seizures. Primary objective has been to identify the efficacy of AEDs in perioperative seizure prophylaxis. Secondary objective has been to highlight the most common type of post-operative AEDs. Methods All available studies from 2000-2021 including randomized or non-randomized clinical trials, prospective or retrospective observational cohort studies, and case series of six or more cases that address these criteria have been collected. Results Our search concluded that the most common type of post-operative seizure is the Early seizure which is of total 87 patients representing 12.3% of seizure reported patients, yet when comparing the P-value between the Early & late seizure it has a P-value of 0.415 which is nonsignificant rendering the comparison redundant. The Most common types of AED used are Phenytoin (PHT) 89 (71.8%) & Levetiracetam (LEV) 109 (81.8%). To measure the efficacy of AEDs two groups of patients with no history of AED administration or seizures preoperatively were created, one the control group of 268 participants were not administered AEDs postoperatively only 32 (11.94%) of them suffered from seizures postoperatively. The other group of 171 participants were administered the AEDs postoperatively only 25 (14.62%) of these participants suffered from postoperative seizure. Comparing both of these results statistically it had a P-value of 0.416 which is non-Significant statistically. On interpreting these results was that the AED have no influence in controlling the seizures. Conclusion Postoperative seizures are one of the main complications of brain tumor surgery. Neurosurgeons have a strong belief more of tradition that preventing seizures with Anti-Epileptic Drugs (AEDs) as a sort of seizure prophylaxis is not only effective but also necessary. Finally, there is not enough evidence of sufficient quality available to suggest that antiepileptic drugs AEDs treatment can or cannot be recommended to reduce Post-craniotomy seizures.

P-804 Smchd1 is a key regulator of epigenetic cellular memory induced by morphine in mouse embryonic stem cells (mESC)

Abstract Study question Can morphine induce stable epigenetic changes that persist mitotically in mESC? Summary answer SMCHD1 is a key regulator of epigenetic cellular memory induced by morphine, whose deregulation can be memorized by mESC and upon embryo development. What is known already Epigenetic cellular memory induced by environmental factors implies the existence of mitotically heritable changes that influence gene expression without altering DNA sequence, leading to the propagation of heritable changes in phenotype. X chromosome inactivation (XCI) is an important epigenetic process, which takes places during embryo development and is maintained in the adulthood. Since XCI is part of normal development, changes induced by environmental factors might affect embryo development and lead to health problems. As morphine can easily pass through the placental barrier and reach the embryo, our aim is to elucidate whether morphine causes epigenetic regulation on XCI process. Study design, size, duration Epigenetic cellular memory induced by environmental factors implies the existence of mitotically heritable changes that influence gene expression without altering DNA sequence, leading to the propagation of heritable changes in phenotype. To evaluate if morphine can induce cellular epigenetic memory, we analyzed the dynamic epigenetic changes over the time in the absence of morphine. For that purpose, OCT4-reported mESCs were chronically treated with morphine during 24h (10-5 mM) Participants/materials, setting, methods • Transcriptomic analysis by RNA-Sequencing and gene expression validation by qRT-PCR. • Epigenetic analysis by H3K27me3 ChIP-Sequencing and WGBS-Sequencing. • Smchd1 gene silencing by Crisper-Cas9. Main results and the role of chance Morphine induced cellular epigenetic memory upon embryo development. mESCs can memorize morphine exposure and induces transcriptional changes that can persist over the time, even in the absence of morphine. RNA-seq has shown that morphine chronic treatment produces a transcriptional deregulation of 932 genes in P1 just after the treatment and this amount increased after treatment withdrawal (1196 genes, P2 and 2138 in P3). Integrative analyses between P1, P2 and P3 identifies Smchd1 gene as a potential regulator of epigenetic cellular memory induced by morphine. Crisper-Cas9 silencing analyses confirmed that Structural maintenance of chromosomes flexible hinge domain-containing 1 (Smchd1), an architectural factor critical for X-chromosome inactivation (XCI), is a morphine-sensitive target gene. Morphine reduced the gene expression of Smchd1 in mESC at different time points, which is consistent with an increase of H3K27me3 and DNA methylation at promoter. Morphine alters normal X chromosome wide silencing. Our results identified Smchd1 a key regulator of epigenetic cellular memory induced by morphine, whose deregulation can be memorized by the cell, providing an epigenetic mechanism that is maintained into cell-to-cell memory and cell differentiation process, which might cause diseases or health problems during the adulthood. Limitations, reasons for caution To perform the in-vitro analysis in mouse Wider implications of the findings Our results provide insights into the epigenetic mechanisms induced by morphine and establish the bases to understand how environmental factors can cause epigenetic changes that cause health problems or diseases, since a skewed XCI pattern is behind the higher incidence on different neurological diseases such as Alzheimer or Autism Trial registration number not applicable

Long-Term Proton Pump Inhibitor–Acid Suppressive Treatment Can Cause Vitamin B12 Deficiency in Zollinger–Ellison Syndrome (ZES) Patients

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger–Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.

Enhancing Chronic Disease Management: Personalized Medicine Insights from Rural and Urban General Practitioner Practices

Health policies worldwide emphasize managing chronic conditions like diabetes and hypertension through medication and lifestyle modifications. However, translating guidelines into practical application remains challenging, leading to suboptimal care and poor health outcomes, particularly in low-resource settings. This study aims to reveal significant differences between rural and urban patients requiring personalized approaches to chronic disease management based on geographical location and demographic data, considering the impact of emergencies such as the COVID-19 pandemic. Data were collected from rural and urban general practitioner (GP) practices in Poland, covering four years from 2018 to the first quarter of 2021, focusing on diabetes and hypertension epidemiology, risk factors, comorbidities, resource consumption, and disease burden. The findings revealed significant differences between rural and urban patients regarding age, number of patient visits, gender distribution, and types of diagnoses and visit modalities. Rural patients tended to be older, had a higher median number of visits, and exhibited different patterns of diagnoses and visit types compared to urban patients. The study also investigated the impact of the COVID-19 pandemic on chronic disease treatment, finding that while age at visits increased during the pandemic, there were no significant changes in gender distribution, but a noticeable shift in diagnoses and visit modalities with an increase in remote visits and changes in the prevalence of specific diagnoses. These disparities highlight the need for tailored approaches to chronic disease management based on geographic location and patient demographics. The study underscores the importance of understanding the unique challenges and opportunities in managing chronic diseases across different settings and during public health crises like the COVID-19 pandemic, aiding healthcare providers and policymakers in developing targeted interventions to improve chronic disease prevention and management, ultimately leading to better health outcomes for individuals and communities. Further research is needed to explore the long-term effects of the pandemic on chronic disease treatment and assess the effectiveness of interventions to mitigate its impact.

Research progress on pathogenesis of chronic fatigue syndrome and treatment of traditional Chinese and Western medicine

Chronic Fatigue Syndrome (CFS) is a complex and perplexing medical disorder primarily characterized by persistent and debilitating fatigue, often accompanied by a constellation of symptoms, including weakness, dyspnea, arthromyalgia, sore throat, and disrupted sleep patterns. CFS is defined by its persistent or recurrent manifestation for a minimum duration of six months, marked by an enduring and unrelenting fatigue that remains refractory to rest. In recent decades, this condition has garnered significant attention within the medical community. While the precise etiology of CFS remains elusive, it is postulated to be multifactorial. CFS is potentially associated with various contributory factors such as infections, chronic stress, genetic predisposition, immune dysregulation, and psychosocial influences. The pathophysiological underpinnings of CFS encompass viral infections, immune system dysregulation, neuroendocrine aberrations, heightened oxidative stress, and perturbations in gut microbiota. Presently, clinical management predominantly relies on pharmaceutical interventions or singular therapeutic modalities, offering alleviation of specific symptoms but exhibiting inherent limitations. Traditional Chinese Medicine (TCM) interventions have emerged as a promising paradigm, demonstrating notable efficacy through their multimodal, multi-target, multi-pathway approach, and holistic regulatory mechanisms. These interventions effectively address the lacunae in contemporary medical interventions. This comprehensive review synthesizes recent advancements in the understanding of the etiological factors, pathophysiological mechanisms, and interventional strategies for CFS, drawing from a corpus of domestic and international literature. Its aim is to furnish valuable insights for clinicians actively involved in diagnosing and treating CFS, as well as for pharmaceutical researchers delving into innovative drug development pathways. Moreover, it seeks to address the intricate challenges confronted by clinical practitioners in managing this incapacitating condition.

Risk factors determining adherence to tyrosine kinase inhibitors in chronic myeloid leukaemia.

Tyrosine kinase inhibitors (TKIs) have successfully changed the natural course of chronic myeloid leukaemia (CML). Although they are highly effective drugs, their clinical benefit is conditioned by adherence. This study aims to analyse the adherence of CML patients treated with TKIs and to identify the main factors influencing their adherence to TKIs treatment. An 8-month prospective, observational, multicentre study which included patients diagnosed with CML on treatment with TKIs attending the outpatient departments (OPD) of the Pharmacy Services of the participating hospitals. Adherence was assessed using two methods: the Simplified Medication Adherence Questionnaire (SMAQ) and the register of treatment dispensations from the OPDs. To analyse the predictors of adherence, a questionnaire was developed to report demographic and socio-economic information on the patients. A total of 130 patients enrolled in this study. Adherence rate was 56.9% (n = 74) among individuals, not conditioned by the type of drug used: imatinib (54.8%), nilotinib (63.6%) or dasatinib (54.3%) (p = 0.67). The patient educational level (p = 0.047) and employment status (p = 0.028) were predictors of non-adherence to treatment. Adherence is one of the most relevant parameters affecting the effectiveness of highly effective chronic treatments. Approximately half of our patients showed inadequate adherence to treatment with TKIs, with employment status and the individual's level of education emerging as the determining factors.

Hyperglycemia impairs EAAT2 glutamate transporter trafficking and glutamate clearance in islets of Langerhans: implications for type 2 diabetes pathogenesis and treatment.

Pancreatic endocrine cells employ a sophisticated system of paracrine and autocrine signals to synchronize their activities, including glutamate, which controls hormone release and β-cell viability by acting on glutamate receptors expressed by endocrine cells. We here investigate whether alteration of the excitatory amino acid transporter 2 (EAAT2), the major glutamate clearance system in the islet, may occur in type 2 diabetes mellitus and contribute to β-cell dysfunction. Increased EAAT2 intracellular localization was evident in islets of Langerhans from T2DM subjects as compared with healthy control subjects, despite similar expression levels. Chronic treatment of islets from healthy donors with high-glucose concentrations led to the transporter internalization in vesicular compartments and reduced [H3]-d-glutamate uptake (65 ± 5% inhibition), phenocopying the findings in T2DM pancreatic sections. The transporter relocalization was associated with decreased Akt phosphorylation protein levels, suggesting an involvement of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the process. In line with this, PI3K inhibition by a 100-µM LY294002 treatment in human and clonal β-cells caused the transporter relocalization in intracellular compartments and significantly reduced the glutamate uptake compared to control conditions, suggesting that hyperglycemia changes the trafficking of the transporter to the plasma membrane. Upregulation of the glutamate transporter upon treatment with the antibiotic ceftriaxone rescued hyperglycemia-induced β-cells dysfunction and death. Our data underscore the significance of EAAT2 in regulating islet physiology and provide a rationale for potential therapeutic targeting of this transporter to preserve β-cell survival and function in diabetes.NEW & NOTEWORTHY The glutamate transporter SLC1A2/excitatory amino acid transporter 2 (EAAT2) is expressed on the plasma membrane of pancreatic β-cells and controls islet glutamate clearance and β-cells survival. We found that the EAAT2 membrane expression is lost in the islets of Langerhans from type 2 diabetes mellitus (T2DM) patients due to hyperglycemia-induced downregulation of the phosphoinositide 3-kinase/Akt pathway and modification of its intracellular trafficking. Pharmacological rescue of EAAT2 expression prevents β-cell dysfunction and death, suggesting EAAT2 as a new potential target of intervention in T2DM.

MyD88 Signaling Accompanied by Microbiota Changes Supports Urinary Bladder Carcinogenesis

Urinary bladder cancer (BC) inflicts a significant impairment of life quality and poses a high mortality risk. Schistosoma haematobium infection can cause BC, and the urinary microbiota of BC patients differs from healthy controls. Importantly, intravesical instillation of the bacterium Bacillus Calmette-Guerin stands as the foremost therapy for non-muscle invasive BC. Hence, studying the receptors and signaling molecules orchestrating bacterial recognition and the cellular response in the context of BC is of paramount importance. Thus, we challenged Toll-like receptor 4 (Tlr4) and myeloid differentiation factor 88 (Myd88) knock-out (KO) mice with N-butyl-N-(4-hydroxylbutyl)-nitrosamine (BBN), a well-known urinary bladder carcinogen. Gut microbiota, gene expression, and urinary bladder pathology were followed. Acute exposure to BBN did not reveal a difference in bladder pathology despite differences in the animal’s ability to recognize and react to bacteria. However, chronic treatment resulted in reduced cancer invasiveness among Myd88KO mice while the absence of functional Tlr4 did not influence BC development or progression. These differences correlate with a heightened abundance of the Faecalibaculum genus and the lowest microbial diversity observed among Myd88KO mice. The presented data underscore the important role of microbiota composition and MyD88-mediated signaling during bladder carcinogenesis.

Effects of Chronic Exposure to Low Doses of Rotenone on Dopaminergic and Cholinergic Neurons in the CNS of Hemigrapsus sanguineus

Rotenone, as a common pesticide and insecticide frequently found in environmental samples, may be present in aquatic habitats worldwide. Exposure to low concentrations of this compound may cause alterations in the nervous system, thus contributing to Parkinsonian motor symptoms in both vertebrates and invertebrates. However, the effects of chronic exposure to low doses of rotenone on the activity of neurotransmitters that govern motor functions and on the specific molecular mechanisms leading to movement morbidity remain largely unknown for many aquatic invertebrates. In this study, we analyzed the effects that rotenone poisoning exerts on the activity of dopamine (DA) and acetylcholine (ACh) synthesis enzymes in the central nervous system (CNS) of Asian shore crab, Hemigrapsus sanguineus (de Haan, 1835), and elucidated the association of its locomotor behavior with Parkinson’s-like symptoms. An immunocytochemistry analysis showed a reduction in tyrosine hydroxylase (TH) in the median brain and the ventral nerve cord (VNC), which correlated with the subsequent decrease in the locomotor activity of shore crabs. We also observed a variation in cholinergic neurons’ activity, mostly in the ventral regions of the VNC. Moreover, the rotenone-treated crabs showed signs of damage to ChAT-lir neurons in the VNC. These data suggest that chronic treatment with low doses of rotenone decreases the DA level in the VNC and the ACh level in the brain and leads to progressive and irreversible reductions in the crab’s locomotor activity, life span, and changes in behavior.

Isothiocyanate-Corticosteroid Conjugates against asthma: Unity makes strength

Asthma is a major noncommunicable disease, affecting both children and adults, and represents one of the major causes leading to high health care costs due to the need for chronic pharmacological treatments. The standard gold therapy of inflammation in asthmatic patients involves the use of glucocorticoids even if their chronic use is often related to serious adverse effects. Growing evidence suggests the biological relevance of hydrogen sulfide (H2S) in the pathogenesis of airway diseases. Hence, aiming to associate the beneficial effects of steroidal anti-inflammatory drugs (SAIDs) to H2S biological activity, we designed and synthesized novel multi-target molecules by chemically combining a group of glucocorticoids, usually employed in asthma treatment, with an isothiocyanate moiety, well-known for its H2S releasing properties. Firstly, the synthesized compounds have been screened for their H2S-releasing profile using an amperometric approach and for their in vitro effects on the degranulation process, using RBL-2H3 cell line. The physicochemical profile, in terms of solubility, chemical and enzymatic stability of the newly hybrid molecules, has been assessed at different physiological pH values and in esterase-rich medium (bovine serum albumin, BSA). The selected compound 5c, through both its corticosteroid and H2S releasing component, has been evaluated in vivo in experimental model of asthma. The compound 5c inhibited in vivo all asthma features with a significative effect on the restoration of pulmonary structure and reduction of lung inflammation.

Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner.

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD + can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD + precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice. Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD + metabolism. Together, these data show that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD + boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

Development and validation of a nomogram to predict poor efficacy of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients.

Imatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system. We retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores. The area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778-0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P<0.05). We constructed a nomogram that can be effectively used to predict the efficacy of imatinib in patients with newly diagnosed CML-CP based on a single center, 10-year retrospective cohort study.

Diaphragm and Lung Transplantation.

Mutual interactions between the diaphragm and lung transplantation (LTx) are known to exist. Before LTx, many factors can exert notable impact on the diaphragmatic function, such as the underlying respiratory disease, the comorbidities, and the chronic treatments of the patient. In the post-LTx setting, even the surgical procedure itself can cause a stressful trauma to the diaphragm, potentially leading to morphological and functional alterations. Conversely, the diaphragm can significantly influence various aspects of the LTx process, ranging from graft-to-chest cavity size matching to the long-term postoperative respiratory performance of the recipient. Despite this, there are still no standard criteria for evaluating, defining, and managing diaphragmatic dysfunction in the context of LTx to date. This deficiency hampers the accurate assessment of those factors which affect the diaphragm and its reciprocal influence on LTx outcomes. The objective of this narrative review is to delve into the complex role the diaphragm plays in the different stages of LTx and into the modifications of this muscle following surgery.

Characterization of Anti-GAD65-Associated Neurological Syndromes: Clinical Features and Antibody Titers

Introduction: Anti-GAD65 antibodies are associated with several neurological phenotypes. Antibody titers are increasingly recognized as useful in diagnosis and prognosis. Objective: To describe a Portuguese cohort of patients with anti-GAD65-associated neurological syndromes. Methods: Retrospective analysis of all patients with positive anti-GAD65 antibodies and associated neurological syndromes followed in a tertiary referral center. Results: Nineteen anti-GAD65 antibody-positive neurological patients were identified, 62.3% female, with a mean age of onset of 56.0 (SD = 13.3) years. Comorbid autoimmune disorders were present in seven patients. Six patients had limbic encephalitis (31.6%), four had epilepsy (21.1%), four had cerebellar ataxia (21.1%), and three had stiff-person syndrome (15.8%). Two patients presented with isolated cognitive dysfunction (executive and mnesic) in the absence of other neurological symptoms. The mean follow-up time was 24.0 (14.0–42.0) months, at the end of which the mean modified Rankin Scale (mRS) value was 2.0 (1.0–4.0). Screening for malignancies was negative in all patients. Serum quantitative analysis was carried out in 18 patients, 10 of whom showed titers above previously defined cut-off points (&gt;10,000 IU/L for ELISA and &gt;20 mmol/L for RIA). Quantitative CSF analysis was performed in nine patients, with four showing above-threshold titers. There was no association between anti-GAD65 levels and clinical phenotype or the final mRS values. High-dose intravenous methylprednisolone and oral prednisolone were the most common acute and chronic treatment regimens, respectively. Conclusion: Anti-GAD65 antibodies are associated with varied neurological syndromes, and antibody titers alone should not be used to exclude a disease.