Therapeutic Alternatives Research Articles

Prognostic Prediction and Immune Microenvironment Characterization in Uveal Melanoma: A Novel Mitochondrial Metabolism-Related Gene Signature.

Uveal Melanoma (UM), a highly aggressive and metastatic intraocular cancer with a strong propensity for liver metastasis, presents limited therapeutic alternatives and unfavorable survival outcomes. Despite its low incidence, the underlying mechanisms of UM pathogenesis and the precise role of mitochondrial metabolism in UM remain inadequately understood. Utilizing Cox proportional hazards regression analysis was used to assess prognostic relevance, and consensus clustering was employed for molecular subtyping. A risk signature was constructed using Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. We further conducted comparative analyses on clinicopathological characteristics, somatic mutation profiles, drug sensitivity, gene expression patterns, and tumor microenvironment features across different molecular subtypes. Moreover, a nomogram was developed and evaluated. Among 1234 mitochondria metabolism-related genes (MMRGs), 343 were identified as significantly associated with the prognosis of UM. These prognosis-associated MMRGs facilitated the classification of UM into two distinct molecular subtypes, which displayed notable differences in prognosis and pathological staging. Furthermore, an index termed the MMRGs-derived index (MMI) was derived from eight MMRGs, serving as a quantitative measure for poor prognosis risk in UM. MMI demonstrated significant associations with clinicopathological characteristics, somatic mutations, drug responsiveness, and the tumor microenvironment, where higher MMI levels corresponded to worse prognosis, advanced pathological stages, and increased immune cell infiltration. The nomogram built upon MMI provided a potential tool for clinical prognosis assessment in UM patients. This study demonstrated the potential value of MMRGs in predicting prognosis and molecular stratification within UM; however, additional clinical and basic research is warranted to validate their applicability and elucidate the related mechanisms.

Successful treatment of Crohn's disease-related peripheral spondyloarthritis with upadacitinib: two case reports and case-based review.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease (CD), not only causes significant intestinal inflammation but also leads to extra-intestinal manifestations such as spondyloarthritis (SpA). Although the efficacy of tumor necrosis factor (TNF) inhibitors has been reported for IBD-related SpA, some cases still encounter treatment failure, highlighting the need for novel therapeutic alternatives. Recently, Janus kinase inhibitors have demonstrated their efficacy in IBD and SpA, yet their impact on CD-related SpA remains unexplored. Here we present the first two cases of CD-related peripheral SpA successfully treated with upadacitinib. Additionally, our literature review identified a reported case of CD-related peripheral SpA treated with tofacitinib. All cases achieved clinical remission of both CD and peripheral SpA with Janus kinase inhibitors, and no adverse events or disease relapses were reported during the observation period. Our cases and literature review highlight the promising potential of Janus kinase inhibitors as a novel treatment not only for intestinal inflammation of CD, but also for CD-related peripheral SpA.

Genome-Scale Metabolic Models in Fungal Pathogens: Past, Present, and Future.

Fungi are diverse organisms with various characteristics and functions. Some play a role in recycling essential elements, such as nitrogen and carbon, while others are utilized in the food and drink production industry. Some others are known to cause diseases in various organisms, including humans. Fungal pathogens cause superficial, subcutaneous, and systemic infections. Consequently, many scientists have focused on studying the factors contributing to the development of human diseases. Therefore, multiple approaches have been assessed to examine the biology of these intriguing organisms. The genome-scale metabolic models (GEMs) have demonstrated many advantages to microbial metabolism studies and the ability to propose novel therapeutic alternatives. Despite significant advancements, much remains to be elucidated regarding the use of this tool for investigating fungal metabolism. This review aims to compile the data provided by the published GEMs of human fungal pathogens. It gives specific examples of the most significant contributions made by these models, examines the advantages and difficulties associated with using such models, and explores the novel approaches suggested to enhance and refine their development.

Proanthocyanidin Regulates NETosis and Inhibits the Growth and Proliferation of Liver Cancer Cells - In Vivo, In Vitro and In Silico Investigation.

Liver cancer ranks third in global cancer-related mortality, with about 700,000 deaths recorded yearly, making it one of the most common cancers worldwide. Even though prognoses differ according to the severity of the diseases, many patients now exhibit an increased life cycle since the implementation of chemotherapy. In the current study, we investigated the effect of proanthocyanidin ‒a polyphenol molecule found in many plants‒ on the proliferation and invasion of liver cancer cells. In particular, we determined the effect of proanthocyanidin on the serum levels of four strategic liver cancer target, TNFα, IL-6, cfDNA, and IL-1β. Further molecular insight on the inhibitory mechanism of proanthocyanidin against TNFα, IL-6, and IL-1β was obtained via molecular docking, molecular dynamics simulations and binding free energy calculations. Results showed that proanthocyanidin inhibited the growth of HepG2 and HEP3B cells, and effectively reduced clonogenic survival and invasion potential when compared to control cells. Proanthocyanidin was also found to suppress the expression of Bcl-2 (26 kDa) protein in HepG2 cells, while increasing the expression of Bax (21 kDa). Molecular dynamics (MD) and thermodynamic binding free energy calculations showed that proanthocyanidin maintained stable binding within the active site of target proteins across the entire 100 ns MD simulation period, and its binding affinity outscored respective control molecules.In conclusion, the multifaceted analysis showcased in this study demonstrated promising anti-cancer effect of proanthocyanidin on HepG2 and HEP3B cancer cells, highlighting its potential as a viable liver cancer therapeutic alternative.

Antiretroviral therapy combined with Shenling Guben Granules for the treatment of HIV infection with immune reconstitution deficiency: A randomized, double-blind, placebo-controlled study

Background: Even with long-term complete suppression of the virus through Antiretroviral therapy (ART), people infected with HIV cannot attain optimal immune reconstitution. This phenomenon is called immune reconstitution deficiency, there are no effective therapeutic interventions for immune reconstitution deficiency in modern medicine. Objective: To evaluate the efficacy and safety of ART with Shenling Guben Granules Traditional Chinese medicine in boosting immunological reconstitution compared with ART alone. Methods: This was a randomized, double-blind, placebo-controlled, multi-center clinical trial evaluating the efficacy and safety of ART combined with Chinese medicine. The individuals aged 18–65 years with poor immune reconstitution following ART were included in this trial. The primary outcome was a change in the absolute value of CD4+ T lymphocytes after 72 weeks of combined ART and Chinese medicine administration. Secondary outcomes included changes in CD4+ T lymphocyte functional subpopulations, activated T lymphocyte subpopulations, CD4+ T lymphocyte proliferation, and T lymphocyte apoptosis from baseline to after 72 weeks. We also evaluated efficacy at 24- and 48-week intervals to better understand the dynamics of the trial drug’s efficacy. Results: There was a significant increase in CD4+ cell counts in groups treated with the Shenling Guben Granules after 24 weeks, 48 weeks, and 72 weeks of treatment (P<0.05), and the difference in CD4+ cell counts at 24 weeks of treatment was statistically significant (P=0.010). After 48 and 72 weeks of therapy, the CD4+CD38+ cell counts in the Shenling Guben Granules group were significantly higher than in the control group (P<0.05). In the subgroup analysis of CD4+ cell counts ≥200 cells/mm3, the CD4+ cell counts in the treatment group were higher than the control group after treatment for 24, 48, and 72 weeks (P<0.05). Discussion: CD4 cell counts in HIV/AIDS patients with immunological reconstitution insufficiency can be improved to a certain extent using Shenling Guben Granules. The greater the CD4 cell count at the start, the better the therapy response. Furthermore, Shenling Guben Granules have the efficacy and safety to prevent aberrant immunological activation. A large sample size, long-term follow-up, and multiple efficacy indicators were employed to assess the therapy’s safety. Our findings will lead to new therapeutic alternatives for HIV/AIDS patients suffering from immune reconstitution deficiency. Clinical Trial Registry: Name of the registry: Sundy on promote the reconstruction of Inadequate responders in HIV/AIDS patients after combined antiretroviral therapy by Shen Ling Gu Ben Granules;Chictr.org.cn Identifier: ChiCTR1800015290, registered on March 21, 2018( http://www.chictr.org.cn/registry.aspx).

Evaluating alternative compounds for strongyloidiasis therapy: Novel insights from larval migration inhibition test.

Strongyloidiasis is a neglected tropical disease estimated to affect more than 600 million people worldwide. Recently, the World Health Organization road map on neglected tropical diseases 2021-2030 has put the focus on strongyloidiasis, including this disease within its mass drug administration campaigns. With the use of ivermectin in extensive treatment of all populations at-risk, identifying effective therapeutic alternatives is crucial in case ivermectin resistance arises. The objective of the present study was the development of a larval migration inhibition assay to evaluate the anthelmintic efficacy of commercial drugs and diamine and aminoalcohol derivatives against infective Strongyloides ratti third stage larvae. Through this technique, we successfully screened and estimated the in vitro anthelmintic efficacy of six commercial drugs, seven diamine derivatives and eight aminoalcohol derivatives. Unexpectedly, the half-maximal effective concentration of ivermectin and moxidectin (2.21 and 2.34 μM, respectively) were observed as the highest value obtained among all commercial drugs tested by this in vitro technique. Moreover, some diamine and aminoalcohol derivatives showed superior efficacy inhibiting S. ratti motility compared to ivermectin, with five compounds (AA23, AA34, AO2 AO7 and AO14b) also displaying selectivity indexes on HepG2 and Caco2 higher than 1. These findings underscore the potential of these derivatives as promising alternatives for strongyloidiasis treatment, warranting further investigation and in vivo efficacy assessment.

A Holistic View on Erectile Dysfunction: South African Medicinal Plants as Sustainable Alternative Therapies

Erectile dysfunction is a common problem affecting men worldwide, especially as they age. This condition is characterized by the inability to achieve or maintain an erection firm enough for sexual intercourse and may result from various factors, including vascular, neurogenic, hormonal, and psychological. Common first-line treatment options for the disease have relied on phosphodiesterase-5 inhibitors such as sildenafil (Viagra), which are costly, inaccessible, and sometimes result in adverse health effects. Consequently, there has been increasing interest in exploring medicinal plants as alternative remedies because of their easy access and affordability. In South Africa, 75 plant species with properties that affect testosterone levels, luteinizing hormone, and follicle-stimulating hormone are used as aphrodisiacs. Some plant extracts can increase blood testosterone concentrations and stimulate penile erection by maintaining nitric oxide levels. This paper presents current information about the possible utilization of South African medicinal plants as viable and readily available therapeutic alternatives for managing erectile dysfunction. In addition, it discusses in detail the various mechanisms of action of medicinal plants in managing the disease. The information on the efficacy of African medicinal plants in managing erectile dysfunction provided in this review will help increase awareness of the sustainable use of natural products. It may serve as a basis for including indigenous herbal remedies in the guidelines for erectile dysfunction management as potential treatment options in Africa.

Identifying prothrombin and bone sialoprotein as potential drug targets for idiopathic pulmonary fibrosis

BackgroundIdiopathic Pulmonary Fibrosis (IPF) is a fatal disease with scarce therapeutic alternatives, which imposes a significant economic burden on society. The identification of novel drug targets is thus critically essential. Plasma proteins with discernible causal evidence hold promise as viable drug targets for this condition.MethodsWe performed a proteome-wide Mendelian randomization (MR) analysis to assess the causal effects of 4,907 circulating proteins from the deCODE study on the risk of IPF from the Finngen Database (2,018 cases vs. 373,064 controls). We further replicated the MR analysis in 1426 proteins from the ARIC study and IPF from the UK Biobank (1,369 cases vs. 435,866 controls). Then a series of analyses including Bayesian colocalization, Steiger filtering, and phenotype scanning were conducted to validate the credibility of the MR results. Subsequently, protein-protein interaction (PPI) analysis, pathway enrichment analysis, and druggability assessment were executed to elucidate the underlying mechanisms. Finally, the findings were corroborated using a bleomycin-induced pulmonary fibrosis mouse model.ResultsThe MR analysis bolstered by robust evidence of colocalization, indicated a significant positive association between Prothrombin and increased IPF risk (OR = 3.26,95%CI 1.75–6.07). Conversely, Bone Sialoprotein (IBSP) demonstrated an inverse association with IPF susceptibility (OR = 0.27,95%CI 0.14–0.55).ConclusionsThe integrative analysis suggests that Prothrombin and IBSP are promising candidates as potential drug targets for IPF. Additional clinical investigations are warranted to substantiate these findings.

Balanitis of Zoon treated with 30% salicylic acid lotion – A case series

Balanitis of Zoon or balanitis circumscripta plasmacellularis is a non-venereal balanitis affecting middle-aged uncircumcised men. It follows a benign protracted course with a minimal tendency for spontaneous resolution. Chronicity of disease and genital distribution is sufficient to evoke anxiety among subjects and is the primary reason for dermatological consultation. Many topical modalities (antibiotics, antifungals, and immunomodulators) have been resorted to as therapeutic measures with variable and unsatisfactory results and recurrences. Circumcision is a definitive and curative treatment. However, 30% salicylic acid (SA) lotion can prove to be a promising therapeutic alternative, especially for subjects reluctant for circumcision. We are presenting a case series of 10 patients with balanitis of the Zoon treated with 30% SA lotion.

Current Overview of Spinocerebellar Ataxia Type 7 in Mexican Population: Challenges in Specialized Care for a Rare Disease.

Spinocerebellar ataxia type 7 (SCA7) is a rare genetic disease characterized by progressive cerebellar syndrome and macular degeneration. In a previous study, we clinically and genetically characterized a group of Mexican patients, which represented one of the largest cohorts of SCA7 patients worldwide and demonstrated that all patients had a unique genetic origin. Our laboratory developed a program for the diagnosis, medical care, and long-term follow-up of these patients living in Veracruz State, and in this report, we present an update to this research, covering 2013 to 2024. So far, we identified 172 SCA7 carriers, with a few cases outside Veracruz, and our data support that the length of the CAG repeat tract mainly determines disease severity and life expectancy, and accordingly, we define three different phenotypes, early-onset (EO), classical-onset (CO), and late-onset (LO), with EO patients showing the lowest life expectancy. Furthermore, we found that parental transmission of mutant alleles leads to increased CAG repeat instability, compared to maternal ones. Interestingly, a haplotype analysis revealed that patients outside Veracruz may have different genetic origins. In conclusion, longitudinal observations of SCA7 patients provide insight into the natural history of SCA7 and help to design strategies for diagnosis, genetic counseling, physical rehabilitation, and therapeutic alternatives.

Paternal perinatal depression: underestimation of the disorder, its clinical and classificatory entanglements, and therapeutic alternatives

In the perinatal period, fathers may also suffer from depression, referred to as paternal perinatal depression. Studies have shown that the prevalence of paternal perinatal depression is considerably higher than in the general adult population. For example, a meta-analysis showed that the prevalence of depression among fathers was 9.76% during the prenatal period and 8.75% during the postpartum year.1 Paternal perinatal depression can deteriorate the marital relationship and generate psychosocial and behavioral problems in the offspring (Ramchandani et al., 2021).2 However, paternal perinatal depression has received comparatively little clinical attention. A review of the literature on this subject will list the biological, psychological and social risk factors for this condition, which include a history of depression or anxiety disorders, lack of social support, conflicts in the couple's relationship, economic and labor problems. The clinical characteristics of depression share similarities with depressions in other periods of life, and there are differential clinical features, such as anger, aggressiveness, somatic symptoms and greater comorbidity with substance abuse disorder. Early detection with scales such as the Edinburgh, Gotland and PAPA and the appropriate approach are fundamental to mitigate the effects of paternal perinatal depression. Psychotherapeutic support, psychoeducation of the disorder, and self-care tools can be part of a comprehensive approach to help parents experiencing this condition. In conclusion, the proposal to include this disorder within the parental perinatal affective disorders, as proposed by the author Baldoni,3 given the level of overlap that it usually has with other comorbid conditions (anxiety, alcohol abuse, impulse control disorders) and high frequency of masked symptoms, goes in the direction to give the attention it deserves for early detection and provide adequate support and treatment.

The Use of Midazolam as an Antiseizure Medication in Neonatal Seizures: Single Center Experience and Literature Review.

Existing therapeutic alternatives for neonatal crises have expanded in recent decades, but no consensus has been reached on protocols based on neonatal seizures. In particular, little is known about the use of midazolam in newborns. The aim of our study is to evaluate the response to midazolam, the appearance of side effects, and their impact on therapeutic decisions. This is a STROBE-conformed retrospective observational study of 10 patients with neonatal seizures unresponsive to common antiseizure drugs, admitted to San Marco University Hospital's neonatal intensive care (Catania, Italy) from September 2015 to October 2022. In our database search, 36 newborns were treated with midazolam, but only ten children met the selection criteria for this study. Response was assessed both clinically and electrographic. Only 4 patients at the end of the treatment showed a complete electroclinical response; they were full-term infants with a postnatal age greater than 7 days. Non-responders and partial responders are all premature (4/10) or full-term neonates who started therapy in the first days of life (< 7th day) (2/10). Neonatal seizures in preterm show a lower response rate to midazolam than seizures in full-term infants, with poorer prognosis. Liver and renal function and central nervous system development are incomplete in premature infants and the first days of life. In this study, we show that midazolam, a short-acting benzodiazepine, appears to be most effective in full-term infants and after 7 days of life.

Gabapentin Dosing Guidance: a Multimodal Approach to Topical and Oral Concomitant Therapy

As researchers in pain management search for safer alternatives to oral analgesics, transdermal or externally applied analgesic options are becoming increasingly available. The search for therapeutic alternatives is fueled by not only the risk of misuse of opioids and similar CNS depressant drugs, but also the impact that chronic pain has on a patient’s quality of life. In this review, we determine an approach by which topical and oral gabapentin can be used safely and effectively, either as monotherapy, or as synergistic concomitant therapy.

Applications of plant-derived extracellular vesicles in medicine.

Plant-derived extracellular vesicles (EVs) are promising therapeutic agents owing to their natural abundance, accessibility, and unique biological properties. This review provides a comprehensive exploration of the therapeutic potential of plant-derived EVs and emphasizes their anti-inflammatory, antimicrobial, and tumor-inhibitory effects. Here, we discussed the advancements in isolation and purification techniques, such as ultracentrifugation and size-exclusion chromatography, which are critical for maintaining the functional integrity of these nanovesicles. Next, we investigated the diverse administration routes of EVs and carefully weighed their respective advantages and challenges related to bioavailability and patient compliance. Moreover, we elucidated the multifaceted mechanisms of action of plant-derived EVs, including their roles in anti-inflammation, antioxidation, antitumor activity, and modulation of gut microbiota. We also discussed the impact of EVs on specific diseases such as cancer and inflammatory bowel disease, highlighting the importance of addressing current challenges related to production scalability, regulatory compliance, and immunogenicity. Finally, we proposed future research directions for optimizing EV extraction and developing targeted delivery systems. Through these efforts, we envision the seamless integration of plant-derived EVs into mainstream medicine, offering safe and potent therapeutic alternatives across various medical disciplines.

SHOULD ANTI-CGRP MONOCLONAL ANTIBODIES ALWAYS BE THE DRUG OF FIRST CHOICE FOR MIGRAINE PROPHYLAXIS IN BRAZIL? - A PHARMACOECONOMIC STUDY

Efficacy (success of therapy under ideal conditions), efficiency (the relationship between the costs and outcomes of a specific intervention), and effectiveness (the balance between efficacy and efficiency in clinical practice) are measures used to evaluate health interventions. Thus, in private practice and the public health system, the knowledge of these pharmacoeconomic data should influence the appropriate treatment choice. Migraine prophylaxis falls within this context. Traditional medications are available in the public health system, while galcanezumab is not routinely available. The present study aims to analyze the efficacy and effectiveness of galcanezumab and traditional therapeutic alternatives (amitriptyline, divalproex sodium, and topiramate). Efficacy data were obtained from the relevant literature (PubMed) and cost values from the ABCFARMA magazine. The economic impact analysis considered the cost of living for an economically active adult in Brazil based on the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística, IBGE) and the Institute for Applied Economic Research (Instituto de Pesquisa Econômica Aplicada, IPEA). Efficacy: amitriptyline: 40%; divalproex sodium: 30%; topiramate: 31%; galcanezumab: 50%. Their annual costs were: amitriptyline R$ 240.00; sodium divalproate R$ 876.00; topiramate R$ 600.00; galcanezumab R$ 13,992.00. Efficiency: amitriptyline 200%; divalproex sodium 41.1%; topiramate 62%; galcanezumab 4%. Ultimately, effectiveness is amitriptyline 120%; divalproex sodium 35.7%; topiramate 46.5%; galcanezumab 27%. Galcanezumab is the most effective; however, in a broader analysis, where payers, availability, and patient conditions are considered, evaluating efficacy alone may not be feasible in practical contexts and, therefore, anti-CGRP antibodies will not always be the first-line medications in migraine prophylaxis.

Impacto da farmácia verde de Ipatinga – MG na redução das prescrições de Benzodiazepínicos em unidades de saúde pública.

Phytotherapy as a therapeutic alternative is the context of the study on Anxiolytic Herbal Medicines in the reduction of Benzodiazepine prescriptions (BZDs). The verification was developed from the analysis of the quantity dispensed with BZDs compared to the dispensing of anxiolytic Herbal Medicines from the Green Pharmacy of Ipatinga - MG. The data correspond to the dispensations, year-on-year from 2013 to 2019, in ten Health Units with phytotherapy. Clonazepam 2.5 mg/ml and Diazepam 10 mg are BZDs. Lavender Tincture, Chamomile, Holy Grass, Passion Fruit and Melissa; correspond to anxiolytic Herbal Medicines. From 2013 to 2017, the dispensation of anxiolytic herbal medicines increased by an average of 12.686% while BZD prescriptions reduced by an average of 6.957%. The trend was interrupted with the ban of the Green Pharmacy by the health surveillance, in August 2018. The objective is to verify the impact of anxiolytic Herbal Medicines in the reduction of BZDs prescriptions in Health Units with phytotherapy in Ipatinga - MG, within the Scope of SUS.

Design, synthesis, and evaluation of dual son of sevenless 1 (SOS1) and epidermal growth factor receptor (EGFR) inhibitors for the treatment of cancers

The treatment of KRAS mutant tumors remains challenging and dual-targeted small-molecule drugs are considered to be innovative therapeutic alternatives. Herein, we discovered a series of SOS1 and EGFR dual inhibitors by employing a fused pharmacophore strategy and structural optimization. Notably, compound 4 exhibited potent SOS1 (IC50 = 8.3 nM) and EGFR (IC50 = 14.6 nM) inhibitory activities and markedly inhibited the proliferation of other KRAS-mutant cancer cell lines. Furthermore, Western blot analysis confirmed that compound 4 effectively reduced the level of downstream p-ERK. These results indicated that compound 4 could serve as a potential compound for treating KRAS mutant tumors.

Natural Autophagy Activators to Fight Age-Related Diseases.

The constant increase in the elderly population presents significant challenges in addressing new social, economic, and health problems concerning this population. With respect to health, aging is a primary risk factor for age-related diseases, which are driven by interconnected molecular hallmarks that influence the development of these diseases. One of the main mechanisms that has attracted more attention to aging is autophagy, a catabolic process that removes and recycles damaged or dysfunctional cell components to preserve cell viability. The autophagy process can be induced or deregulated in response to a wide range of internal or external stimuli, such as starvation, oxidative stress, hypoxia, damaged organelles, infectious pathogens, and aging. Natural compounds that promote the stimulation of autophagy regulatory pathways, such as mTOR, FoxO1/3, AMPK, and Sirt1, lead to increased levels of essential proteins such as Beclin-1 and LC3, as well as a decrease in p62. These changes indicate the activation of autophagic flux, which is known to be decreased in cardiovascular diseases, neurodegeneration, and cataracts. The regulated administration of natural compounds offers an adjuvant therapeutic alternative in age-related diseases; however, more experimental evidence is needed to support and confirm these health benefits. Hence, this review aims to highlight the potential benefits of natural compounds in regulating autophagy pathways as an alternative approach to combating age-related diseases.

Late mitral leaflet tear after transcatheter edge-to-edge repair for acute ischemic mitral regurgitation: a case report

Abstract Background Acute mitral regurgitation due to papillary muscle rupture is a severe complication of acute myocardial infarction. Transcatheter edge-to-edge repair is emerging as an effective alternative to surgical treatment, with encouraging outcomes. Leaflet adverse events are rare and are associated with relapse of significant mitral regurgitation. Case summary A 54-year-old man arrived at our hospital with a late presentation of ST-elevation myocardial infarction. During primary percutaneous coronary intervention of the circumflex coronary artery, a partial papillary muscle rupture occurred with acute severe mitral regurgitation and cardiogenic shock. Due to the severe hemodynamic instability, the patient underwent an emergent transcatheter edge-to-edge repair with MitraClip device during Impella support with mitral regurgitation resolution and hemodynamic stabilization. At 2-month follow-up an interclip leaflet tear occurred with relapse of severe mitral regurgitation, requiring a mitral valve replacement surgery. Discussion Acute mitral regurgitation due to papillary muscle rupture is a serious complication of acute myocardial infarction. Management is based on hemodynamic stabilization and surgery. The transcatheter edge-to-edge repair is emerging as a therapeutic alternative in high-risk cases. Leaflet adverse events rarely occur during the transcatheter edge-to-edge repair procedure or before patient discharge. Our case is the first to report a late leaflet adverse event, occurring two months after the procedure and, interestingly, after an acute myocardial infarction conditioning an ischemic mitral regurgitation. This event may be the result of the progressive adverse remodeling of left ventricular inferolateral akinetic wall, with consequent increase of tethering forces on the posterior leaflet, tensioned in the opposite direction by the clip.

Mechanisms of Resistance to Rituximab Used for the Treatment of Autoimmune Blistering Diseases

Autoimmune blistering diseases represent a group of chronic severe, disabling, and potentially fatal disorders of the skin and/or mucous membranes, primarily mediated by pathogenic auto-antibodies. Despite their rarity, these diseases are associated with significant morbidity and mortality and profound negative impact on the patient’s quality of life and impose a considerable economic burden. Rituximab, an anti-CD-20 monoclonal antibody, represents the first line of therapy for pemphigus, regardless of severity and a valuable off-label therapeutic alternative for subepidermal autoimmune blistering diseases as it ensures high rates of rapid, long-lasting complete remission. Nevertheless, disease recurrence is the rule, all patients requiring maintenance therapy with rituximab eventually. While innate resistance to rituximab in pemphigus patients is exceptional, acquired resistance is frequent and may develop even in patients with initial complete response to rituximab, representing a real challenge for physicians. We discuss the various resistance mechanisms and their complex interplay, as well as the numerous therapeutic alternatives that may be used to circumvent rituximab resistance. As no therapeutic measure is universally efficient, individualization of rituximab treatment regimen and tailored adjuvant therapies in refractory autoimmune blistering diseases are mandatory.