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Revista Espanola de Enfermedades... Dec 2023Tofacitinib is an oral small molecule JAK inhibitor approved for the treatment of moderate to severe ulcerative colitis (UC). Its efficacy and safety have been...
Tofacitinib is an oral small molecule JAK inhibitor approved for the treatment of moderate to severe ulcerative colitis (UC). Its efficacy and safety have been demonstrated in phase III clinical trials and supported by real-life data. We report the case of an 18-year-old woman with a 1-year diagnosis of left-sided UC, with multiple admissions due to disease exacerbation or infections, refractory to infliximab (with azathioprine) and currently under treatment with vedolizumab and tacrolimus. She was admitted due to a severe disease exacerbation and, because of a previous history of neuropsychiatric side effects to corticotherapy, tofacitinib was initiated. In the following 6 days, there was no clinical improvement of UC, and serial blood work-up revealed moderate grade persistent peripheral eosinophilia (3000 cells/mm3) and acute kidney injury grade 1 KDIGO. Tofacitinib temporary suspension was decided, with a rapid normalization of renal function/eosinophil levels. Tofacitinib was restarted 2 days after its suspension. However, she developed moderate eosinophilia (2000 cells/mm3) again, which was considered an adverse effect (AE) to tofacitinib, leading to its suspension with eosinophilia resolution. Given the severity of the disease, after a multidisciplinary discussion, it was decided to start high-dose corticotherapy and ustekinumab with maintenance therapy every 4 weeks, and to add tacrolimus. Clinical and biochemical remission were achieved, and the patient was discharged. Three-month follow-up after tofacitinib suspension showed no recrudescence of eosinophilia. Tofacitinib represents a significant advance in the management of UC patients. The drug has a good safety profile with few related AE. This case aims to warn about an adverse reaction to tofacitinib not reported so far, including in a multicenter real-life setting recently published by Hernández et al where eosinophilia is also not described, thus emphasizing the rarity of this AE. To our knowledge this is the first case of tofacitinib-induced eosinophilia in the context of UC. .
Topics: Female; Humans; Adolescent; Tacrolimus; Treatment Outcome; Colitis, Ulcerative; Eosinophilia; Disease Progression
PubMed: 37539549
DOI: 10.17235/reed.2023.9831/2023 -
MBio Oct 2023Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1...
Dengue virus (DENV) is a major human pathogen that can cause hemorrhagic fever and shock syndrome. One important factor of DENV pathogenicity is non-structural protein 1 (NS1), a glycoprotein that is secreted from infected cells. Here we study the mode of action of the widely used drug ivermectin, used to treat parasitic infections and recently shown to lower NS1 blood levels in DENV-infected patients. We found that ivermectin blocks the nuclear transport of transcription factors required for the expression of chaperones that support the folding and secretion of glycoproteins, including NS1. Impairing nuclear transport of these transcription factors by ivermectin or depleting them from infected cells dampens NS1 folding and thus its secretion. These results reveal a novel mode of action of ivermectin that might apply to other flaviviruses as well.
Topics: Humans; Dengue Virus; Dengue; Endoplasmic Reticulum Chaperone BiP; Ivermectin; Karyopherins; Molecular Chaperones; Transcription Factors; Viral Nonstructural Proteins
PubMed: 37702492
DOI: 10.1128/mbio.01441-23 -
Frontiers in Cellular and Infection... 2023Traditional drug susceptibility testing cannot be performed in clinical laboratories due to the slow-growing characteristics of when cultured . Sanger sequencing is the...
BACKGROUND
Traditional drug susceptibility testing cannot be performed in clinical laboratories due to the slow-growing characteristics of when cultured . Sanger sequencing is the standard method for detecting drug resistance-associated mutations. It has been used in some laboratories to guide the choice of macrolide antibiotics for infected patients. Furthermore, resistance to fluoroquinolone has become another emerging clinical challenge.
OBJECTIVE
Sequencing analysis can detect unknown mutations, but it is time-consuming, requires professional analytical skills and the appropriate testing equipment. The main objective of this study was to establish a nested real-time PCR method for the simultaneous detection of and genotypes in relation to the macrolide and fluoroquinolone resistance.
RESULTS
105 MG-positive samples and 27 samples containing other pathogens were used for validation. The limit of the nested real-time PCR detection was 500 copies/reaction and there was no cross-reaction with , , , , , , and , but the assay cross-reacted with . Compared with sequencing results, the sensitivity of was 100% (95% CI; 93.3 -100), the specificity was 94.3% (95% CI; 79.4 - 99.0), the overall consistency was 98% (95% CI; 92.5 - 99.7) and value was 0.96 ( < 0.001); the sensitivity of was 100% (95% CI; 93.4 - 100), the specificity was 89.7% (95% CI; 71.5 - 97.3) and the overall consistency was 96.9% (95% CI; 90.7 - 99.2) with a value of 0.92 ( < 0.001).
CONCLUSIONS
The results of this sensitive and rapid alternative for identifying resistant genotypes of are intuitive and easy to interpret, especially for mixed MG populations. Although the relevant primers need further adjustment, this reliable method would provide an effective diagnostic tool for the selection of antibiotics in clinical practice.
Topics: Humans; Fluoroquinolones; Mycoplasma genitalium; RNA, Ribosomal, 23S; Real-Time Polymerase Chain Reaction; Macrolides; Microbial Sensitivity Tests; Drug Resistance, Bacterial; Mycoplasma Infections; Mycobacterium tuberculosis; Anti-Bacterial Agents; Mutation
PubMed: 37928183
DOI: 10.3389/fcimb.2023.1271392 -
The Lancet. Microbe Jun 2024
Topics: Humans; China; Pneumonia, Mycoplasma; Macrolides; Mycoplasma pneumoniae; Anti-Bacterial Agents; Drug Resistance, Bacterial
PubMed: 38244553
DOI: 10.1016/S2666-5247(23)00405-6 -
Cancer Letters Jul 2023Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed...
Multiple myeloma (MM) is an incurable malignancy of plasma cells. Ivermectin is a US Food and Drug Administration-approved drug for antiparasitic use. Here, we showed that ivermectin exerted anti-MM effects and significantly synergized with proteasome inhibitors in vitro and in vivo. Ivermectin alone exhibited mild anti-MM activity in vitro. Further investigation suggested that ivermectin inhibited proteasome activity in the nucleus by repressing the nuclear import of proteasome subunits, such as PSMB5-7 and PSMA3-4. Therefore, ivermectin treatment caused the accumulation of ubiquitylated proteins and the activation of the UPR pathway in MM cells. Furthermore, ivermectin treatment caused DNA damage and DNA damage response (DDR) signaling pathway activation in MM cells. Ivermectin and bortezomib exhibited synergized anti-MM activity in vitro. The dual-drug treatment resulted in synergistic inhibition of proteasome activity and increased DNA damage. An in vivo study using a human MM cell line xenograft mouse model showed that ivermectin and bortezomib efficiently repressed MM tumor growth in vivo, while the dual-drug treatment was well tolerated by experimental animals. Overall, our results demonstrated that ivermectin alone or cotreated with bortezomib might be promising in MM treatment.
Topics: Humans; Animals; Mice; Proteasome Inhibitors; Bortezomib; Multiple Myeloma; Proteasome Endopeptidase Complex; Ivermectin; Disease Models, Animal; Cell Line, Tumor; Antineoplastic Agents
PubMed: 37149018
DOI: 10.1016/j.canlet.2023.216218 -
International Journal of Biological... 2023Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding...
Benign prostatic hyperplasia (BPH) is a condition that becomes more common with age and manifests itself primarily as the expansion of the prostate and surrounding tissues. However, to date, the etiology of BPH remains unclear. In this respect, we performed single-cell RNA sequencing of prostate transition zone tissues from elderly individuals with different prostate volumes to reveal their distinct tissue microenvironment. Ultimately, we demonstrated that a reduced Treg/CD4+ T-cell ratio in the large-volume prostate and a relatively activated immune microenvironment were present, characterized partially by increased expression levels of granzymes, which may promote vascular growth and profibrotic processes and further exacerbate BPH progression. Consistently, we observed that the prostate gland of patients taking immunosuppressive drugs usually remained at a smaller volume. Furthermore, in mouse models, we confirmed that both suppression of the immune system with rapamycin and induction of Treg proliferation with low doses of IL-2 therapy indeed prevented the progression of BPH. Taken together, our findings suggest that an activated immune microenvironment is necessary for prostate volume growth and that Tregs can reverse this immune activation state, thereby inhibiting the progression of BPH.
Topics: Humans; Male; Animals; Mice; Prostatic Hyperplasia; Interleukin-2; Sirolimus; Prostate; Disease Models, Animal
PubMed: 37497009
DOI: 10.7150/ijbs.85089 -
Clinical Infectious Diseases : An... Nov 2023Mycoplasma genitalium (MG) is on the CDC Watch List of Antimicrobial Resistance Threats, yet there is no systematic surveillance to monitor change.
BACKGROUND
Mycoplasma genitalium (MG) is on the CDC Watch List of Antimicrobial Resistance Threats, yet there is no systematic surveillance to monitor change.
METHODS
We initiated surveillance in sexual health clinics in 6 cities, selecting a quota sample of urogenital specimens tested for gonorrhea and/or chlamydia. We abstracted patient data from medical records and detected MG and macrolide-resistance mutations (MRMs) by nucleic acid amplification testing. We used Poisson regression to estimate adjusted prevalence ratios (aPRs) and 95% CIs, adjusting for sampling criteria (site, birth sex, symptom status).
RESULTS
From October-December 2020 we tested 1743 urogenital specimens: 57.0% from males, 46.1% from non-Hispanic Black persons, and 43.8% from symptomatic patients. MG prevalence was 16.6% (95% CI: 14.9-18.5%; site-specific range: 9.9-23.5%) and higher in St Louis (aPR: 1.9; 1.27-2.85), Greensboro (aPR: 1.8; 1.18-2.79), and Denver (aPR: 1.7; 1.12-2.44) than Seattle. Prevalence was highest in persons <18 years (30.4%) and declined 3% per each additional year of age (aPR: .97; .955-.982). MG was detected in 26.8%, 21.1%, 11.8%, and 15.4% of urethritis, vaginitis, cervicitis, and pelvic inflammatory disease (PID), respectively. It was present in 9% of asymptomatic males and 15.4% of asymptomatic females, and associated with male urethritis (aPR: 1.7; 1.22-2.50) and chlamydia (aPR: 1.7; 1.13-2.53). MRM prevalence was 59.1% (95% CI: 53.1-64.8%; site-specific range: 51.3-70.6%). MRMs were associated with vaginitis (aPR: 1.8; 1.14-2.85), cervicitis (aPR: 3.5; 1.69-7.30), and PID cervicitis (aPR: 1.8; 1.09-3.08).
CONCLUSIONS
MG infection is common in persons at high risk of sexually transmitted infections; testing symptomatic patients would facilitate appropriate therapy. Macrolide resistance is high and azithromycin should not be used without resistance testing.
Topics: Female; Humans; Male; Anti-Bacterial Agents; Urethritis; Mycoplasma genitalium; Uterine Cervicitis; Sexual Health; Macrolides; Drug Resistance, Bacterial; Pelvic Inflammatory Disease; Vaginitis; Mycoplasma Infections; Prevalence
PubMed: 37402645
DOI: 10.1093/cid/ciad405 -
Alternative Therapies in Health and... Nov 2023To analyze the use of antimicrobial drugs in patients during the COVID-19 pandemic. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To analyze the use of antimicrobial drugs in patients during the COVID-19 pandemic.
METHODS
We searched for literature about antimicrobial treatment in COVID-19 patients through the Cochrane Library, Embase, PubMed, the Chinese biomedical literature database, CNKI, the Chinese journal full-text database, Wanfang, and Vipu. The quality evaluation of the literature was performed by Jadad's quality score.
RESULTS
A total of three articles reported on ivermectin treatment in patients with COVID-19, and the Meta-analysis showed no clinical and statistical heterogeneity among the studies (I2 = 15%, P = .31), a fixed effect model was used to incorporate effect sizes. The clinical effect of the observed group was not different from the control group (P = .16). None of the three ivermectin articles with clinical effect as the effect indicator showed a significant difference (P > .05), suggesting no publication bias. A total of four publications reported the treatment with azithromycin in patients with COVID-19, and the Meta-analysis showed no clinical and statistical heterogeneity between the studies (I2 = 0%, P = .88), using a fixed-effect model to incorporate the effect sizes. The clinical effect of the observed group was not different from the control group (P = .57). None of the four azithromycin articles with a clinical effect as the effect index was statistically significant (P > .05), suggesting no publication bias.
CONCLUSION
During the COVID-19 pandemic, the patient's use of antibiotics does not significantly improve clinical efficacy, so antibiotic use is recommended only for patients with complicated bacterial infections.
Topics: Humans; COVID-19; Azithromycin; Pandemics; Ivermectin; Anti-Bacterial Agents
PubMed: 37708540
DOI: No ID Found -
Respiratory Investigation Mar 2024The evidence for macrolide therapy in adult asthma is not properly established and remains controversial. We conducted a systematic review and meta-analysis to examine... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The evidence for macrolide therapy in adult asthma is not properly established and remains controversial. We conducted a systematic review and meta-analysis to examine the efficacy and safety of macrolide therapy for adult asthma.
METHODS
We searched randomized controlled trials from MEDLINE via the PubMed, CENTRAL, and Ichushi Web databases. The primary outcome was asthma exacerbation. The secondary outcomes were serious adverse events (including mortality), asthma-related quality of life (symptom scales, Asthma Control Questionnaire, and Asthma Quality of Life Questionnaire), rescue medication (puffs/day), respiratory function (morning peak expiratory flow, evening peak flow, and forced expiratory volume in 1 s), bronchial hyperresponsiveness, and minimum oral corticosteroid dose. Of the 805 studies, we selected seven studies for the meta-analysis, which was conducted using a random-effects model.
SYSTEMATIC REVIEW REGISTRATION
University Hospital Medical Information Network Clinical Trials Registry (UMIN000050824).
RESULTS
No significant difference between macrolide and placebo for asthma exacerbations was observed (risk ratio 0.71, 95 % confidence interval [CI] 0.46-1.09; p = 0.12). Macrolide therapy for adult asthma showed a significant improvement in rescue medication with short-acting beta-agonists (mean difference -0.41, 95 % CI -0.78 to -0.04; p = 0.03). Macrolide therapy did not show more serious adverse events (odd ratio 0.61, 95 % CI 0.34-1.10; p = 0.10) than those with placebo. The other secondary outcomes were not significantly different between the macrolide and placebo groups.
CONCLUSIONS
Macrolide therapy for adult asthma may be more effective than placebo and could be a treatment option.
Topics: Adult; Humans; Macrolides; Quality of Life; Disease Progression; Asthma; Anti-Bacterial Agents; Adrenal Cortex Hormones
PubMed: 38211545
DOI: 10.1016/j.resinv.2023.12.015 -
Pharmacological Research Sep 2023Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.
Topics: Humans; Everolimus; Tuberous Sclerosis; Sirolimus; Mechanistic Target of Rapamycin Complex 1
PubMed: 37549757
DOI: 10.1016/j.phrs.2023.106884