48,322 research outputs found

    Population pharmacokinetic analysis of transdermal granisetron in healthy Chinese and Caucasian volunteers

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    Granisetron patches are a prolonged delivery transdermal system that is used to prevent Chemotherapy-induced nausea and vomiting (CINV). To date, no pharmacokinetics comparison between Chinese and Caucasian populations has been conducted for granisetron patches. This study focused on the ethnic differences in pharmacokinetics (PK) of granisetron transdermal delivery system (GTDS) between Chinese and Caucasians and the influence of demographic covariates on pharmacokinetics (age, weight, height, body mass index, sex). To achieve this, blood concentration data were collected from 112 Caucasian healthy subjects participating in four clinical trials and 24 Chinese healthy subjects from one clinical trial, after a single application of the granisetron transdermal delivery system. A nonlinear mixed-effects model method of Phoenix NLME software was used to establish a population pharmacokinetic (Pop PK) model for Caucasian subjects. Bootstrap and visual predictive check (VPC) were used to validate the model. Based on the analysis a one-compartment model with first-order absorption and a first-order elimination well described the PK characteristics of GTDS. The apparent systemic clearance was determined to be 31316.3 mL/h and the central compartment volume of distribution was 6299.03 L. None of the five covariates (age, weight, height, body mass index, and sex) included in the Pop PK were significant covariates affecting PK. The final Pop PK model was used to simulate the Caucasian blood concentration by applying the dosing regimen used for the Chinese population. Comparison of the simulated Caucasian PK data with observed clinical PK data from Chinese healthy subjects revealed no significant differences in the main parameters, AUClast and Cavg, between the two groups. These findings suggested that no dose adjustment was required when applied to the Chinese population. In conclusion, this Pop PK study comparing the transdermal patch in Chinese and Caucasian healthy subjects provided valuable insights for optimizing dosage across ethnicities

    Late-Onset Neuromyelitis Optica Spectrum Disorder Mimicking a Non-Arteritic Anterior Ischemic Optic Neuropathy–Case Report

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    A 60-year-old white woman presented to the emergency department with painless decrease of visual acuity in the left eye (LE). The diagnosis of a non-arteritic anterior ischemic optic neuropathy in the LE was established based on the clinical picture and the results of static perimetry, fluorescein angiography, visual evoked potential, and magnetic resonance imaging (MRI) of the brain and orbit. Six months later, the patient reported visual impairment in the right eye (RE). Best corrected visual acuity (BCVA) in the RE was 5/10. Gadolinium-enhanced MRI showing inflammation of both optic nerves and the optic chiasm in correlation with positivity for immunglobulin G antibody against aquaporin-4 led to the diagnosis of late-onset neuromyelitis optica spectrum disorder. High-dose intravenous methylprednisolone therapy followed by oral tapering was administered and oral azathioprine was started to reduce the risk of further relapse. At discharge, BCVA was 5/5 in the RE. The patient remains under the care of neurology and ophthalmology clinics, with no recurrences for two years. The possibility of neuromyelitis optica spectrum disorder with optic neuritis in older patients is important in the differential diagnosis of ischemic optic neuropathy

    "Lesion journey" in hidradenitis suppurativa: clinical and ultrasonographic correlations

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    Introduzione: L'idrosadenite suppurativa (HS) è una malattia immuno-mediata che colpisce i follicoli piliferi situati principalmente nelle aree ricche di ghiandole apocrine. Materiali e metodi: È stato condotto uno studio osservazionale prospettico monocentrico finalizzato a correlare i parametri clinici ed ecografici con: l'evoluzione delle lesioni, la probabilità di riacutizzazione o di andare incontro ad un trattamento chirurgico/laser-CO2. Risultati: Sono stati reclutati sessantuno pazienti con un'età media pari a 29,5 ± 7,5 anni che presentavano un numero basale di 127 noduli infiammatori, 43 ascessi e 62 fistole. Dopo un tempo medio di 77,9 settimane, rispettivamente il 40%, 14%, 8% di noduli, ascessi e fistole erano guariti, il 5%, 30%, 29% persistevano privi di infiammazione, il 47%, 33%, 63 % presentava uno stato infiammatorio, e l'8% e il 23% dei noduli e degli ascessi erano evoluti in fistole. Sono stati registrati 137 episodi di flare nelle lesioni acute (noduli + ascessi) e 54 nelle lesioni croniche (fistole), mentre il numero di interventi procedurali è stato rispettivamente pari a 59 e 50. I fattori predittivi associati ad un'evoluzione sfavorevole (stato infiammatorio o cronicizzazione) per ascessi e noduli sono stati: evidenza ecografica di frammenti piliferi intralesionali, elevato segnale Power Doppler (PD) ed edema all'ecografia, profondità della localizzazione ed interessamento genitale; i predittori associati alle fistole sono stati: profondità della localizzazione, edema e dimensioni della lesione. La probabilità che una lesione acuta venisse sottoposta ad un intervento procedurale è stata correlata a: età, presenza di frammenti piliferi, segnale PD, edema e profondità della localizzazione; per le fistole l'unico predittore indipendente è stato la dimensione. I predittori di riacutizzazione della patologia per ascessi e noduli sono stati: giovane età all'esordio, segnale PD, evidenza ecografica di frammenti follicolari, profondità della localizzazione e dimensioni; per le fistole i predittori sono stati: localizzazione ascellare, profondità della localizzazione, edema e dimensione.Background: Hidradenitis suppurativa (HS) is an immune-mediated disorder affecting hair follicles mainly located in the apocrine gland-bearing area. It presents suppurative lesions consisting of nodules, abscesses, and fistulas that exhibit a variable degree of inflammatory activity. Materials and Methods: A prospective, single-center observational study was designed to correlate clinical and ultrasonographic parameters with the "lesions' evolution" at the end of the study, the probability of flaring or undergoing a surgical/CO2-laser intervention. Results: Sixty-one patients (25 males and 36 females) with a mean age of 29.5±7.5 years who had a total baseline number of 127 inflammatory nodules, 43 abscesses, and 62 fistulas were recruited. After a mean follow-up time of 77.9 weeks, 40%, 14%, 8% of nodules, abscesses, and fistulas respectively had healed, 5%, 30%, 29% were free of inflammation, 47%, 33%, 63% had an inflammatory status, and 8% and 23% of nodules and abscesses had evolved into fistulas. There were 137 flare episodes in the acute lesions (nodules + abscesses) and 54 in the chronic lesions (fistulas), while the number of procedural interventions was 59 and 50, respectively. The predictive factors associated with an unfavorable evolution (inflammatory status or chronicity) for abscesses and nodules were: presence of hair tracts, high degree of Power Doppler (PD) and edema on ultrasonography, depth of localization and genital body area; for fistulas the predictors were: depth of localization, edema, and size. The probability of an acute lesion going to procedural intervention correlated with: age, presence of hair tracts, high degree of PD, edema, and depth of localization; for fistulas the only independent predictor was size. The predictors of flare for abscesses and nodules were: young age at disease onset, PD signal, hair tracts, depth of localization, and size; in the case of fistulas the predictors were: axillary localization, depth of localization, edema, and size

    Nuclear shape instability caused by lamin A deregulation promotes invasiveness in pediatric bone sarcomas: from nucleo-cytoskeleton dynamics to novel therapeutic opportunities

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    Osteosarcoma (OS) and Ewing sarcoma (EWS) are the two most frequent primary bone tumors, in which metastases remain the most relevant adverse prognostic factor. Lamin A is the main constituent of the nuclear lamina, with a fundamental role in maintaining the connection between nucleus and cytoskeleton (through LINC complex proteins interactions), and its alterations can be implicated in tumor progression. We investigated how nucleo-cytoskeleton dynamics is influenced by lamin A modulation in OS and EWS, demonstrating that both these cancer models had low levels of lamin A, which are linked to a significantly more marked nuclear misshaping. In our in vitro studies, reduced levels of lamin A promoted migratory abilities in these tumors. Moreover, these findings were corroborated by gene expression analyses on EWS patient samples, showing that LMNA levels were significantly lower in metastatic lesions compared to primary tumors and that patients with low LMNA had a significant worse overall survival. We also found that LMNA expression significantly impaired EWS metastases formation in vivo. We demonstrated that low lamin A expression was linked to a severe mislocalization of LINC complex proteins, thus disrupting nucleo-cytoskeleton interactions, with a corresponding gain in malignant properties, which resulted in increased invasiveness. Lamin A overexpression or its accumulation by a statin-based pharmacological treatment allowed us to reconstitute a functional nucleo-cytoskeleton interplay, which resulted in significant downmodulation of ROCK2 and YAP, two crucial drivers of EWS aggressiveness. Our study demonstrated that lamin A is a favorable mediator of nuclear shape stability in bone sarcomas, and its modulation rescues LINC complex protein localization and regulates mechano-signaling pathways, thus promoting a less aggressive cancer phenotype. We also identified statins, already employed in clinical practice, as a tool capable to increase lamin A levels, and to reconstitute functional nucleo-cytoskeletal dynamics, resulting in reduced cellular migration

    Cesarean scar ectopic pregnancy - case series. Diagnosis and treatment at tertiary care hospital

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    Cesarean Scar Pregnancy is a rare form of ectopic pregnancy with the incidence increasing due to the increased rate of primary cesarean section. It is potentially life-threatening and can cause serious maternal morbidity and mortality if undetected or misdiagnosed. The aim of this case series is to study clinical presentation, diagnosis, and treatment of caesarean scar pregnancy. We studied 10 confirmed cases of cesarean scar pregnancy treated in department of OBGYN at a tertiary care hospital, in western India over a period of 2 years. Maternal age ranged between 25 years to 38 years and gestational age ranged between 6 weeks to 10 weeks. Seven patients presented with symptoms like bleeding per vaginum and/or lower abdominal pain and three patients were asymptomatic. Transvaginal sonography was done for confirmation of diagnosis. In all patients, beta hCG levels were done on the first day. 4 patients were initially treated by medical management but was unsuccessful. Surgical management was done by laparotomy in 9 patients and in 1 patient laparoscopy. Treatment should beindividualized depending on severity of symptoms, beta hCG level, patient‘s condition, and surgeon‘s experience

    Sociodemographic, nutritional and health status factors associated with adherence to Mediterranean diet in an agricultural Moroccan adult's population

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    Background. Numerous studies have demonstrated beneficial effects of adherence to the Mediterranean diet (MD) on many chronic diseases, including chronic kidney disease (CKD). Objective. The aim of this study was to assess the adherence of a rural population to the Mediterranean diet, to identify the sociodemographic and lifestyle determinants and to analyze the association between adherence to MD and CKD. Material and Methods. In a cross-sectional study, data on sociodemographic, lifestyle factors, clinical, biochemical parameters and diet were collected on a sample of 154 subjects. Adherence to MD was assessed according to a simplified MD score based on the daily frequency of intake of eight food groups (vegetables, legumes, fruits, cereal or potatoes, fish, red meat, dairy products and MUFA/SFA), using the sex specific sample medians as cut-offs. A value of 0 or 1 was assigned to consumption of each component according to its presumed detrimental or beneficial effect on health. Results. According to the simplified MD score, the study data show that high adherence (44.2%) to MD was characterized by intakes high in vegetables, fruits, fish, cereals, olive oil, and low in meat and moderate in dairy. Furthermore, several factors such as age, marital status, education level, and hypertension status were associated with the adherence to MD in the study population. The majority of subjects with CKD have poor adherence to the MD compared to non-CKD with a statistically insignificant difference. Conclusions. In Morocco, maintaining the traditional MD pattern play crucial role for public health. More research is needed in this area to precisely measure this association

    Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

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    Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity

    BCR-ABL1-positive acute lymphoblastic leukemia following successful treatment of acute promyelocytic leukemia: case report

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    Acute promyelocytic leukemia (APL) is currently considered a disease with a higher cure rate. And cases of secondary malignant tumors following successful APL treatment are rare. Here we described a rare case of a 29-year-old man who was treated for APL in 2019 and developed BCR-ABL1-positive acute lymphoblastic leukemia 2 years later. The patient responded well to tyrosine kinase inhibitors and chemotherapy, and achieved a molecular remission. Although APL usually has a good prognosis, the prognosis of its secondary malignancies is uncertain. There are no effective measures to prevent the occurrence of secondary tumors. Continuing to increase the monitoring frequency of laboratory tests, especially the molecular biomarkers, is essential for the diagnosis and treatment of secondary malignancies after the patients achieving complete remission

    Tripterygium glycosides for safely controlling disease activity in systemic lupus erythematosus: a systematic review with meta-analysis and trial sequential analysis

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    Background: Tripterygium glycosides have been used to treat systemic lupus erythematosus (SLE) for a long time, showing the effects of immune regulation. We aimed to evaluate the benefits and risks of Tripterygium Glycosides Tablets (TGT) for patients with SLE.Methods: We searched electronic databases and clinical trial registries for relevant randomized controlled trials (RCTs). We identified eligible RCTs and assessed risk of bias. We conducted a meta-analysis to estimate the pooled effects. The Trial Sequential Analysis (TSA) software was used to verify the reliability of the results.Results: Eight RCTs encompassing 538 patients with SLE were included. TGT combined with conventional treatments (CTs) was superior to CTs alone in reducing lupus activity (MD = −1.66, 95% CI = −2.07 to −1.26, p < 0.00001, low-certainty evidence) and improving overall response rate (ORR) (RR = 1.21, 95% CI = 1.11 to 1.32, p < 0.0001, moderate-certainty evidence). The robustness of the results was confirmed by TSA. Regarding safety, there was no statistical difference in the overall incidence of adverse reactions between the two groups.Conclusion: In patients with SLE, TGT might safely reduce disease activity. However, further high-quality studies are needed to firmly establish the clinical efficacy of TGT.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022300474; Identifier: CRD42022300474
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