Changes in Ergosterol Biosynthesis Alter the Response to Cycloheximide, 4-Nitroquinoline-N-Oxide, Weak Organic Acids, and Virulence in Candida glabrata.

The ERG6 gene encodes the sterol C24-methyltransferase converting zymosterol to fecosterol in the ergosterol biosynthetic pathway. Here, we extend the results of functional analysis of the CgERG6 gene, which was previously shown to modulate drug susceptibility in Candida glabrata mutant cells, by demonstrating that its deletion leads to increased susceptibility to cycloheximide, 4-nitroquinoline-N-oxide and weak organic acids, and such effects are associated with attenuated virulence. Together with abrogated efflux of drug substrates by CgCdr1p and CgPdr12p, the Cgerg6Δ mutation leads to reduced cell surface hydrophobicity and decreased virulence of the mutant cells of C. glabrata. The absence of CgErg6p impacts the lipid organization and function of the plasma membrane, resulting in non-specific permeability and abrogation of normal function of membrane-bound proteins accompanied by decreased virulence in Cgerg6Δ cells. Galleria mellonella larvae were used as a non-vertebrate animal host model to determine differences in the virulence potential of C. glabrata strains (parental strain and the Cgerg6Δ deletion mutant). We found that Cgerg6Δ mutant strain attenuated in virulence caused 25-30% survival of larvae compared with parental strain.

Enhancement of ROS Production by Catechin Is a Primary Effect of Increased Azole Efficacy in Nakaseomyces glabratus (Candida glabrata) Cells Lacking the ERG6 Gene.

Fungal infections have become an important public health problem. Currently, there are only three available classes of antifungals for the treatment of invasive infections. Two of them, azoles and polyenes, target the synthesis of ergosterol or bind to sterols. A promising strategy to improve current therapies is the use of natural compounds in combinational therapies with the existing antifungals. In this work, we analyzed the changes in the susceptibility of the mutant strain of Nakaseomyces glabratus (Candida glabrata) lacking the ERG6 gene (encoding the sterol C-24 methyltransferase in ergosterol biosynthesis) in the presence of catechin and antifungal azoles. The reduced content of ergosterol in the Cgerg6Δ mutant resulted in the increased tolerance of the mutant cells to both azoles and polyenes. The combination of catechin with fluconazole or miconazole led to the growth inhibition of the azole-resistant Cgerg6Δ mutant strain. In the presence of catechin and miconazole, the Cgerg6Δ mutant fails to properly activate the expression of genes encoding the transcription factors CgYap1p and CgMsn4p, as well as the gene expression of CgCTA1, which are involved in oxidative stress response and lead to the intracellular accumulation of ROS. Finally, we show that catechin administration reduces mortality in a Galleria mellonella model infected with C. glabrata. Our work thus supports the use of catechin in combination therapies for fungal infections and shows that the CgERG6 gene could be a potential new drug target.

Therapeutics involved in managing initial and recurrent Clostridium difficile infection: An updated literature review.

Clostridium difficile infection (CDI) has been increasing due to the effect of recurrent hospitalizations. The use of antibiotics has been shown to alter the gut microbiome and lead to CDIs. The treatment is limited to three major antibiotics; however, the incidence of recurrent CDIs has been increasing and drug resistance is a major concern. This aspect is a growing concern in modern medicine especially in the elderly population, critical care patients, and immunocompromised individuals who are at high risk of developing CDIs. Clostridium difficile can lead to various complications including septic shock and fulminant colitis that could prove to be lethal in these patients. Newer modalities of treatment have been developed including bezlotoxumab, a monoclonal antibody and fecal microbiota transplant. There have been studies showing asymptomatic carriers and drug resistance posing a major threat to the healthcare system. Newer treatment options are being studied to treat and prevent CDIs. This review will provide an insight into the current treatment modalities, prevention and newer modalities of treatment and challenges faced in the treatment of CDIs.

Characteristics and distinct prognostic determinants of individuals with hepatosplenic T-cell lymphoma over the past two decades.

BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive peripheral T-cell lymphoma with historically dismal outcomes, representing less than one percent of non-Hodgkin lymphomas. Given its rarity, the true incidence of HSTCL is unknown and most data have been extrapolated through case reports. To the best of our knowledge, the largest and most up to date study addressing the epidemiology and outcomes of patients with HSTCL in the United States covered a period from 1996 to 2014, with a sample size of 122 patients. AIM: To paint the most updated epidemiological picture of HSTCL. METHODS: A total of 186 patients diagnosed with HSTCL, between 2000 and 2017, were ultimately enrolled in our study by retrieving data from the Surveillance, Epidemiology, and End Results database. We analyzed demographics, clinical characteristics, and overall mortality (OM) as well as cancer-specific mortality (CSM) of HSTCL. Variables with a P value < 0.01 in the univariate Cox regression were incorporated into the multivariate Cox model to determine the independent prognostic factors, with a hazard ratio of greater than 1 representing adverse prognostic factors. RESULTS: Male gender was the most represented. HSTCL was most common in middle-aged patients (40-59) and less common in the elderly (80+). Non-Hispanic whites (60.75%) and non-Hispanic blacks (20.97%) were the most represented racial groups. Univariate Cox proportional hazard regression analysis of factors influencing all-cause mortality showed a higher OM among non-Hispanic black patients. CSM was also higher among non-Hispanic blacks and patients with distant metastasis. Multivariate Cox proportional hazard regression analysis of factors affecting CSM revealed higher mortality in patients aged 80 or older and non-Hispanic blacks. CONCLUSION: Overall, the outlook for this rare malignancy is very grim. In this retrospective cohort study of the United States population, non-Hispanic blacks and the elderly had a higher CSM. This data highlights the need for larger prospective studies to investigate factors associated with worse prognosis in one ethnic group, such as treatment delays, which have been shown to increase mortality in this racial/ethnic group for other cancers.

Factors Affecting Survival Outcomes in Neuroendocrine Tumor of the Appendix over the Past Two Decades.

BACKGROUND: Appendiceal neuroendocrine tumors (NETs) rank as the third most frequent neoplasm affecting the appendix, originating from enterochromaffin cells. This study aims to evaluate the influence of various prognostic factors on the mortality rates of patients diagnosed with NETs of the appendix. METHODS: Conducted retrospectively, the study involved 3346 patients, utilizing data sourced from the Surveillance, Epidemiology, and End Results (SEER) database. Our analysis centered on investigating demographic characteristics, clinical features, overall mortality (OM), and cancer-specific mortality (CSM) among the cohort. Variables showing a p-value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox regression analysis. A Hazard Ratio (HR) > 1 indicated an unfavorable prognosis. RESULTS: In the multivariate analysis, higher OM and CSM were observed in males, older age groups, tumors with distant metastasis, poorly differentiated tumors, and those who underwent chemotherapy. Non-Hispanic Black individuals showed elevated mortality rates. CONCLUSION: Delayed diagnosis may contribute to the increased mortality in this community. Improved access to healthcare and treatment is crucial for addressing these disparities. Larger prospective studies are needed to pinpoint the underlying causes of elevated mortality in non-Hispanic Black populations, and randomized controlled trials (RCTs) are warranted to evaluate therapies for advanced-stage appendix NETs.

Ventricular Tachycardia in Patients With Takotsubo Cardiomyopathy: Prevalence, Predictors, and Associated In-Hospital Adverse Events.

Introduction  The purpose of this study was to determine the prevalence of ventricular tachycardia (VT) among patients admitted with takotsubo cardiomyopathy (TCM) as well as to analyze the predictors of VT and the predictors of mortality among patients admitted with TCM. Methods Data were obtained from the National Inpatient Sample (NIS) database from January 2016 to December 2019. Patients with a primary diagnosis of TCM were selected using ICD-10 code I51.81. Subsequently, the study population was divided into patients who developed VT vs. patients who did not develop this complication. We then used multivariate logistic regression to assess the predictors of VT in our patient cohort as well as the predictors of mortality among patients admitted with TCM. Results  Of 40114 patients with TCM, 1923 developed VT (4.8%) during their hospital stay. Predictors of VT include atrial fibrillation (AF) (adjusted odds ratio (aOR): 1.592; 95% confidence interval (CI): 0.00-1.424; p=0.001), congestive heart failure (aOR: 1.451; 95% CI: 1.307-1.610; p=0.001), coagulopathy (aOR: 1.436; 95% CI: 1.150-1.793; p=0.001), and patients who self-identify in the race category as Other (aOR: 1.427; 95% CI: 1.086-1.875; p=0.011). Female sex was found to be protective against VT (aOR: 0.587; 95% CI: 0.526-0.656; p=0.001). Predictors of mortality among patients admitted with TCM include, among other factors, age (aOR: 1.014; 95% CI: 1.011-1.018; p=0.001), Asian or Pacific Islander race (aOR: 1.533; 95% CI: 1.197-1.964; p=0.001), Black race (aOR: 1.242; 95% CI: 1.062-1.452; p=0.007), VT (aOR: 1.754; 95% CI: 1.505-2.045; p=0.001), and AF (aOR: 1.441; 95% CI: 1.301-1.597; p=0.001). Some comorbidities that were protective against mortality in TCM include tobacco use disorder (aOR: 0.558; 95% CI: 0.255-0.925; p=0.028) and obstructive sleep apnea (aOR: 0.803; 95% CI: 0.651-0.990; p=0.028). The female sex was found to be protective against mortality (aOR: 0.532; 95% CI: 0.480-0.590; p=0.001).  Conclusion  In a large cohort of women admitted with TCM, we found the prevalence of VT to be 4.8%. Predictors of VT included conditions such as AF and congestive heart failure. The female sex was found to be protective against VT and protective against mortality among patients admitted with TCM.

Oral mucosa and cutaneous manifestations of psoriasis in an older patient: A case report.

BACKGROUND: Psoriasis is a common cutaneous disease; however, information about psoriasis-related oral mucosal lesions is scarce in the literature. CASE DESCRIPTION: We report a case of a 73-year-old male patient with cutaneous and oral palatal alterations. An incisional biopsy of these lesions revealed psoriasis. CONCLUSION: The current case highlights the importance of a systematic examination of the oral cavity in psoriasis patients for the appropriate diagnosis and management on the control of these lesions.

Evaluating the Utility of Portal Vein Pulsatility Index for Detecting Fluid Unresponsiveness in the Intensive Care Unit.

OBJECTIVE: The primary aim of the authors' study was to evaluate the capacity of the portal vein pulsatility index (PVP) to detect fluid unresponsiveness in patients admitted to intensive care. DESIGN: This was a retrospective, diagnostic accuracy study SETTING: At a tertiary medical-surgical intensive care unit in Buenos Aires, Argentina. PARTICIPANTS: Patients were included during usual care in the intensive care unit, who were evaluated by ultrasonography for the flow of the portal vein, calculating their PVP prior to fluid expansion. INTERVENTIONS: Patients who exhibited an increase of <15% in left ventricle outflow tract velocity-time integral after receiving 500 mL of Ringer Lactate were considered non-responders to fluids. MEASUREMENTS AND MAIN RESULTS: The authors included a total of 63 patients between January 2022 and October 2022. The area under the receiver operating characteristic curve for PVP to predict fluid unresponsiveness was 0.708 (95% CI 0.580 to 0.816). A value of the PVP >32% predicted fluid unresponsiveness with a sensitivity of 30.8% (95% CI 17% to 47.6%) and specificity of 100% (95% CI 85.8 to 100). The positive predictive value was 100%, and the negative predictive value was 47.1% (95% CI 41.9% to 52.3%). CONCLUSIONS: Although PVP has limited value as the sole indicator for fluid management decisions, it can be used as a stopping rule or combined with other diagnostic tests to improve the accuracy of fluid responsiveness assessment.

Essential Role of CgErg6p in Maintaining Oxidative Stress Tolerance and Iron Homeostasis in Candida glabrata.

The human pathogenic fungus Candida glabrata is the second leading cause of candidemia, a life-threatening invasive mycosis. Clinical outcomes are complicated by reduced susceptibility of C. glabrata to azoles together with its ability to evolve stable resistance to both azoles and echinocandins following drug exposure. Compared to other Candida spp., C. glabrata displays robust oxidative stress resistance. In this study, we investigated the impact of CgERG6 gene deletion on the oxidative stress response in C. glabrata. CgERG6 gene encodes sterol-24-C-methyltransferase, which is involved in the final steps of ergosterol biosynthesis. Our previous results showed that the Cgerg6Δ mutant has a lower ergosterol content in its membranes. Here, we show that the Cgerg6Δ mutant displays increased susceptibility to oxidative stress inducing agents, such as menadione, hydrogen peroxide and diamide, accompanied with increased intracellular ROS production. The Cgerg6Δ mutant is not able to tolerate higher concentrations of iron in the growth media. We observed increased expression of transcription factors, CgYap1p, CgMsn4p and CgYap5p, together with increased expression of catalase encoding the CgCTA1 gene and vacuolar iron transporter CgCCC1 in the Cgerg6Δ mutant cells. However, it seems that the CgERG6 gene deletion does not influence the function of mitochondria.

Catechin potentiates the antifungal effect of miconazole in Candida glabrata.

The rising number of invasive fungal infections caused by drug-resistant Candida strains is one of the greatest challenges for the development of novel antifungal strategies. The scarcity of available antifungals has drawn attention to the potential of natural products as antifungals and in combinational therapies. One of these is catechins-polyphenolic compounds-flavanols, found in a variety of plants. In this work, we evaluated the changes in the susceptibility of Candida glabrata strain characterized at the laboratory level and clinical isolates using the combination of catechin and antifungal azoles. Catechin alone had no antifungal activity within the concentration range tested. Its use in combination with miconazole resulted in complete inhibition of growth in the sensitive C. glabrata isolate and a significant growth reduction in the azole resistant C. glabrata clinical isolate. Simultaneous use of catechin and miconazole leads to increased intracellular ROS generation. The enhanced susceptibility of C. glabrata clinical isolates to miconazole by catechin was accompanied with the intracellular accumulation of ROS and changes in the plasma membrane permeability, as measured using fluorescence anisotropy, affecting the function of plasma membrane proteins.

WITHDRAWN: Non-Anti-TNF Biologics as Salvage Therapy for Refractory Acute Severe Ulcerative Colitis, A Systematic Review

Since the authors are not responding to the editor's requests to fulfill the editorial requirement, therefore, the article has been withdrawn.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Health Maintenance and Preventative Care in Inflammatory Bowel Disease: A Systematic Review of the Overall Quality of Societal Recommendations.

BACKGROUND AIMS: Preventative care plays an important role in maintaining health in patients with inflammatory bowel disease (IBD). We aimed to assess the overall quality, strength, and transparency of conflicts among guidelines on preventative care in IBD. METHODS: A systematic literature search was performed in multiple databases to identify all guidelines pertaining to preventative care in IBD in April 2021. All guidelines were reviewed for the transparency of conflicts of interest and funding, recommendation quality and strength, external guideline review, patient voice inclusion, and plan for update-as per Institute of Medicine standards. In addition, recommendations and their quality were compared between societies. RESULTS: Fifteen distinct societies and a total of 89 recommendations were included. Not all guidelines provided recommendations on the key aspects of preventative care in IBD-such as vaccinations, cancer prevention, stress reduction, and diet/exercise. Sixty-seven percent of guidelines reported on conflicts of interest, 20% underwent external review, and 27% included patient representation. In all, 6.7%, 21.3%, and 71.9% of recommendations were based on high, moderate, and low-quality evidence, respectively. Twenty-seven percent, 23.6%, and 49.4% of recommendations were strong, weak/conditional, and did not provide a strength, respectively. The proportion of high-quality evidence ( P =0.28) and strong recommendations ( P =0.41) did not significantly differ across societies. CONCLUSIONS: Many guidelines do not provide recommendations on key aspects of preventative care in IBD. As over 70% of recommendations are based on low-quality evidence, further studies on preventative care in IBD are warranted to improve the overall quality of evidence.

Perfil clínico dos pacientes internados por Covid-19 na unidade de terapia intensiva / Clinical profile of patients hospitalized for Covid-19 in the intensive care unit

Objetivo: identificar o perfil clínico dos pacientes internados por COVID-19 na Unidade de Terapia Intensiva (UTI) de um hospital privado. Métodos: trata-se deum estudo de caráter descritivo, documental, retrospectivo, de corte transversal e análise quantitativa, conduzido em um hospital, no município de Montes Claros, MG, por meio da análise de prontuários de 142 pacientes da UTI com diagnóstico de COVID-19 no período de janeiro de 2020 a abril de 2021. Resultados: dos 142 indivíduos, a média de idadefoi de 64,1 anos, com 58,5% do sexo masculino. Das comorbidades prévias, as que tiveram maior prevalência foram a hipertensão arterial sistêmica com 26,8% e diabetes mellitus com 9,2%. Destes, 133 indivíduos utilizaram ventilação mecânica, com a prevalência de 47,9% no modo ventilação com volume controlado. O tempo médio de internação foi de 6 dias, sendo que 93,7% dos indivíduos foram a óbito, 4,9% receberam alta e 1,4% transferidos para outro hospital. Conclusão: evidenciou-se predominância do sexo masculino, com média de idade de 64,1 anos, o modo ventilatório mais utilizado foi o controlado o volume, com tempo de uso médio de uso 7,9 dias, ou seja, pouco tempo, fato que pode ser justificado pelo alto índice de óbitos na amostra estudada.

Objective: to identify the clinical profile of patients hospitalized for COVID-19 in the Intensive Care Unit (ICU) of a private hospital. Methods: this is a descriptive, documentary, retrospective, cross-sectional study with quantitative analysis conducted in a hospital in the city of Montes Claros, MG, through the analysis of medical records of 142 ICU patients diagnosed with COVID-19 from January 2020 to April 2021. Results: of the 142 individuals, the mean age was 64.1 years, with 58.5% male. Of the previous comorbidities, those with the highest prevalence were systemic arterial hypertension at 26.8% and diabetes mellitus at 9.2%. Of these, 133 individuals used mechanical ventilation, with a prevalence of 47.9% using volume-controlled ventilation. The average length of stay was 6 days, with 93.7% of the individuals dying, 4.9% being discharged, and 1.4% being transferred to another hospital. Conclusion: there was a predominance of males, with an average age of 64.1 years, the most used ventilatory mode was volume-controlled, with an average use time of 7.9 days, that is, a short time, a fact that can be justified by the high rate of deaths in the studied sample.

Erg6p is essential for antifungal drug resistance, plasma membrane properties and cell wall integrity in Candida glabrata.

ERG6 gene encodes C-24 methyltransferase, one of the specific enzymes that differ in mammalian and yeast sterol biosynthesis. To explore the function of CgErg6p in the yeast pathogen Candida glabrata, we have constructed the Cgerg6Δ deletion mutant. We found that C. glabrata cells lacking CgErg6p exhibit reduced susceptibility to both antifungal azoles and polyenes. The reduced content of ergosterol in the Cgerg6 deletion mutant was accompanied by increased expression of genes encoding the last steps of the ergosterol biosynthetic pathway. The absence of CgErg6p leads to plasma membrane hyperpolarization and decrease in its fluidity compared to the parental C. glabrata strain. The absence of sterols containing C-24 alkyls influenced the susceptibility of Cgerg6Δ mutant cells to alkali metal cations and several other metabolic inhibitors. Our results thus show that sterols lacking C-24 alkyls are not sufficient substitutes for maintaining yeast plasma membrane function. The absence of CgErg6p influences also the cell wall integrity and calcineurin signaling in C. glabrata.

Co-targeting CDK2 and CDK4/6 overcomes resistance to aromatase and CDK4/6 inhibitors in ER+ breast cancer.

Resistance to aromatase inhibitor (AI) treatment and combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy (ET) are crucial clinical challenges in treating estrogen receptor-positive (ER+) breast cancer. Understanding the resistance mechanisms and identifying reliable predictive biomarkers and novel treatment combinations to overcome resistance are urgently needed. Herein, we show that upregulation of CDK6, p-CDK2, and/or cyclin E1 is associated with adaptation and resistance to AI-monotherapy and combined CDK4/6i and ET in ER+ advanced breast cancer. Importantly, co-targeting CDK2 and CDK4/6 with ET synergistically impairs cellular growth, induces cell cycle arrest and apoptosis, and delays progression in AI-resistant and combined CDK4/6i and fulvestrant-resistant cell models and in an AI-resistant autocrine breast tumor in a postmenopausal xenograft model. Analysis of CDK6, p-CDK2, and/or cyclin E1 expression as a combined biomarker in metastatic lesions of ER+ advanced breast cancer patients treated with AI-monotherapy or combined CDK4/6i and ET revealed a correlation between high biomarker expression and shorter progression-free survival (PFS), and the biomarker combination was an independent prognostic factor in both patients cohorts. Our study supports the clinical development of therapeutic strategies co-targeting ER, CDK4/6 and CDK2 following progression on AI-monotherapy or combined CDK4/6i and ET to improve survival of patients exhibiting high tumor levels of CDK6, p-CDK2, and/or cyclin E1.

Case Report: Cannabidiol-Induced Skin Rash: A Case Series and Key Recommendations.

Cannabidiol (CBD) is a non-psychotomimetic constituent of the Cannabis plant, with potential therapeutic properties for many physical and neuropsychiatric conditions. Isolated CBD has been suggested to have favorable safety and tolerability. Although CBD-related rash is described, few case reports are well documented in the literature, and usually, CBD was used concomitantly with other medications. Thus, we report four women who presented a skin rash after ongoing CBD use. Other causes of these skin rashes were ruled out after conducting an extensive viral and serological detection panel, and three patients had their lesions biopsied. Two patients were re-exposed to the vehicle (MCT) without developing a new skin rash. Therefore, clinicians must be aware of this potential adverse effect of CBD use.

The UPC2 gene in Kluyveromyces lactis stress adaptation.

KlUpc2p, a transcription factor belonging to the fungal binuclear cluster family, is an important regulator of ergosterol biosynthesis and azole drug resistance in Kluyveromyces lactis. In this work, we show that the absence of KlUpc2p generates Rag- phenotype and modulates the K. lactis susceptibility to oxidants and calcofuor white. The KlUPC2 deletion leads to increased expression of KlMGA2 gene, encoding an important regulator of hypoxic and lipid biosynthetic genes in K. lactis and also KlHOG1 gene. The absence of KlUpc2p does not lead to statistically significant changes in glycerol, corroborating the expression of KlGPD1 gene, encoding NAD+-dependent glycerol-3-phosphate dehydrogenase, that is similar in both the deletion mutant and the parental wild-type strain. Increased sensitivity of Klupc2 mutant cells to brefeldin A accompanied with significant increase in KlARF2 gene expression point to the involvement of KlUpc2p in intracellular signaling. Our observations highlight the connections between ergosterol and fatty acid metabolism to modulate membrane properties and point to the possible involvement of KlUpc2p in K. lactis oxidative stress response.

Generalized verrucosis in GATA2 deficiency successfully treated with systemic acitretin and trichloroacetic acid.

Generalized verrucosis is a clinical manifestation of human papillomavirus infection. Patients with generalized verrucosis present with over 20 verrucae distributed over various anatomical sites. The disorder occurs in association with several genetic syndromes with immunodeficiency, including GATA2 deficiency. We report a 12-year-old boy with GATA2 deficiency and generalized verrucosis that worsened after cyclosporine use following bone marrow transplant. Systemic treatment with acitretin and topical application of trichloroacetic acid, likely along with immune reconstitution, led to complete remission.