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MOTIVATION: Multiplexed immunofluorescence (mIF) is an emerging assay for multichannel protein imaging that can decipher cell-level spatial features in tissues. However, existing automated cell phenotyping methods, such as clustering, face challenges in achieving consistency across experiments and often require subjective evaluation. As a result, mIF analyses often revert to marker gating based on manual thresholding of raw imaging data. RESULTS: To address the need for an evaluable semi-automated algorithm, we developed GammaGateR, an R package for interactive marker gating designed specifically for segmented cell-level data from mIF images. Based on a novel closed-form gamma mixture model, GammaGateR provides estimates of marker-positive cell proportions and soft clustering of marker-positive cells. The model incorporates user-specified constraints that provide a consistent but slide-specific model fit. We compared GammaGateR against the newest unsupervised approach for annotating mIF data, employing two colon datasets and one ovarian cancer dataset for the evaluation. We showed that GammaGateR produces highly similar results to a silver standard established through manual annotation. Furthermore, we demonstrated its effectiveness in identifying biological signals, achieved by mapping known spatial interactions between CD68 and MUC5AC cells in the colon and by accurately predicting survival in ovarian cancer patients using the phenotype probabilities as input for machine learning methods. GammaGateR is a highly efficient tool that can improve the replicability of marker gating results, while reducing the time of manual segmentation. AVAILABILITY AND IMPLEMENTATION: The R package is available at https://github.com/JiangmeiRubyXiong/GammaGateR.
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Algoritmos , Análise de Célula Única , Humanos , Análise de Célula Única/métodos , Software , Processamento de Imagem Assistida por Computador/métodos , Feminino , Neoplasias Ovarianas/metabolismo , Imunofluorescência/métodos , Biomarcadores/metabolismoRESUMO
Acrophialophora is implicated in superficial and invasive infections, especially in immunosuppressed individuals. The present study was undertaken to provide clinical, microbiological, phylogenetic, and antifungal susceptibility testing (AFST) profile of Acrophialophora isolated from India. All the isolates identified as Acrophialophora species at the National Culture Collection for Pathogenic Fungi, Chandigarh, India were revived. Phenotypic and molecular characterization was performed, followed by temperature studies, scanning electron microscopy (SEM), and AFST. We also performed systematic review of all the cases of Acrophialophora species reported till date. A total of nine isolates identified as Acrophialophora species were identified by molecular method as A. fusispora (n = 8) and A. levis (n = 1), from brain abscess (n = 4), respiratory tract (n = 3), and corneal scraping (n = 2). All patients but two had predisposing factors/co-morbidities. Acrophialophora was identified as mere colonizer in one. Temperature studies and SEM divulged variation between both species. Sequencing of the internal transcribed spacer ribosomal DNA and beta-tubulin loci could distinguish species, while the LSU ribosomal DNA locus could not. AFST showed the lowest minimum inhibitory concentrations (MICs) for triazoles and the highest for echinocandins. Systematic literature review revealed 16 cases (11 studies), with ocular infections, pulmonary and central nervous system infections, and A. fusispora was common species. All the patients except three responded well. High MICs were noted for fluconazole, micafungin, and caspofungin. This is the first study delineating clinical, phenotypic, and genotypic characteristics of Acrophialophora species from India. The study highlights microscopic differences between both species and emphasizes the role of molecular methods in precise identification. Triazoles appear to be the most effective antifungals for managing patients.
We describe clinical, phenotypic, and genotypic characteristics of Acrophialophora species. This species causes mild infection to fatal infection in immunosuppressed individuals. Triazoles are effective in treating such infections.
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Antifúngicos , Testes de Sensibilidade Microbiana , Micoses , Filogenia , Índia , Humanos , Antifúngicos/farmacologia , Adulto , Masculino , Micoses/microbiologia , Feminino , Pessoa de Meia-Idade , Ascomicetos/efeitos dos fármacos , Ascomicetos/genética , Ascomicetos/isolamento & purificação , Ascomicetos/classificação , DNA Fúngico/genética , Análise de Sequência de DNA , DNA Espaçador Ribossômico/genética , Microscopia Eletrônica de Varredura , Fenótipo , Tubulina (Proteína)/genética , Idoso , Adulto Jovem , CriançaRESUMO
BACKGROUND: Over the past decades, the increasing incidence of recurrent dermatophytosis associated with terbinafine-resistant Trichophyton has posed a serious challenge in management of dermatophytosis. Independent reports of failure of treatment and high minimum inhibitory concentrations (MIC) of antifungals are available, but data correlating MIC and clinical outcomes is still sparse. Therefore, the present study was conducted to evaluate the outcomes of systemic treatment of dermatophytosis and its correlation with MIC of the etiological agents isolated from such patients. METHODS: Retrospective analysis of 587 consecutive patients with dermatophytosis was done from March 2017 to March 2019. Demographic and clinical details of the patients were noted, along with the results of direct microscopy and fungal culture. The isolates were identified by sequencing the internal transcribed spacer region of rDNA. Antifungal susceptibility testing was performed following the CLSI M38 protocol. Mutation in the squalene epoxidase (SE) gene was detected by DNA sequencing and ARMS-PCR. Based on the culture-positivity and prescribed systemic antifungal, patients were categorised into Group I culture-positive cases treated with systemic terbinafine and Group II culture-positive cases treated with systemic itraconazole, each for a total period of 12 weeks. RESULTS: In the present study, 477 (81.39%) were culture-positive; however, 12 weeks follow-up was available for 294 patients (Group I-157 and Group II-137) who were included for statistical analysis. In both groups [Group I-37/63 (51.4%) and Group II-14/54 (58.3%)], a better cure rate was observed if the initiation of therapy was performed within <6 months of illness. Treatment outcome revealed that if therapy was extended for 8-12 weeks, the odds of cure rate are significantly better (p < .001) with either itraconazole (Odd Ratio-15.5) or terbinafine (Odd Ratio-4.34). Higher MICs for terbinafine were noted in 41 cases (cured-18 and uncured-23) in Group I and 39 cases (cured-16 and uncured-23) in Group II. From cured (Group I-17/18; 94.4% and Group II-14/16; 87.5%) and uncured (Group I-20/23; 86.9% and Group II-21/23; 91.3%) cases had F397L mutation in the SE gene. No significant difference in cure rate was observed in patients with Trichophyton spp. having terbinafine MIC ≥ 1or <1 µg/mL (Group I-p = .712 and Group II-p = .69). CONCLUSION: This study revealed that prolonging terbinafine or itraconazole therapy for beyond 8 weeks rather than the standard 4 weeks significantly increases the cure rate. Moreover, no correlation has been observed between antifungal susceptibility and clinical outcomes. The MIC remains the primary parameter for defining antifungal activity and predicting the potency of antifungal agents against specific fungi. However, predicting therapeutic success based solely on the MIC of a fungal strain is not always reliable, as studies have shown a poor correlation between in vitro data and in vivo outcomes. To address this issue, further correlation of antifungal susceptibility testing (AFST) data with clinical outcomes and therapeutic drug monitoring is needed. It also highlights that initiation of the treatment within <6 months of illness increases cure rates and reduces recurrence. Extensive research is warranted to establish a better treatment regime for dermatophytosis.
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Antifúngicos , Itraconazol , Mutação , Esqualeno Mono-Oxigenase , Terbinafina , Tinha , Trichophyton , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Farmacorresistência Fúngica/genética , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Esqualeno Mono-Oxigenase/genética , Terbinafina/uso terapêutico , Terbinafina/farmacologia , Tinha/tratamento farmacológico , Tinha/microbiologia , Resultado do Tratamento , Trichophyton/efeitos dos fármacos , Trichophyton/genéticaRESUMO
BACKGROUND AND OBJECTIVES: The mechanisms underlying COVID-19-associated pulmonary mucormycosis (CAPM) remain unclear. We use a transcriptomic analysis of the innate immune cells to investigate the host immune and metabolic response pathways in patients with CAPM. PATIENTS AND METHODS: We enrolled subjects with CAPM (n = 5), pulmonary mucormycosis (PM) without COVID-19 (n = 5), COVID-19 (without mucormycosis, n = 5), healthy controls (n = 5) without comorbid illness and negative for SARS-CoV-2. Peripheral blood samples from cases were collected before initiating antifungal therapy, and neutrophils and monocytes were isolated. RNA sequencing was performed using Illumina HiSeqX from monocytes and neutrophils. Raw reads were aligned with HISAT-2 pipeline and DESeq2 was used for differential gene expression. Gene ontology (GO) and metabolic pathway analysis were performed using Shiny GO application and R packages (ggplot2, Pathview). RESULTS: The derangement of core immune and metabolic responses in CAPM patients was noted. Pattern recognition receptors, dectin-2, MCL, FcRγ receptors and CLEC-2, were upregulated, but signalling pathways such as JAK-STAT, IL-17 and CARD-9 were downregulated; mTOR and MAP-kinase signalling were elevated in monocytes from CAPM patients. The complement receptors, NETosis, and pro-inflammatory responses, such as S100A8/A9, lipocalin and MMP9, were elevated. The major metabolic pathways of glucose metabolism-glycolysis/gluconeogenesis, pentose phosphate pathway, HIF signalling and iron metabolism-ferroptosis were also upregulated in CAPM. CONCLUSIONS: We identified significant alterations in the metabolic pathways possibly leading to cellular iron overload and a hyperglycaemic state. Immune responses revealed altered recognition, signalling, effector functions and a pro-inflammatory state in monocytes and neutrophils from CAPM patients.
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COVID-19 , Mucormicose , Humanos , Mucormicose/microbiologia , SARS-CoV-2 , Perfilação da Expressão Gênica , Imunidade InataRESUMO
BACKGROUND: Due to a delay in diagnosis by conventional techniques and high mortality, the development of a standardised and rapid non-culture-based technique is an unmet need in pulmonary, gastrointestinal, and disseminated forms of mucormycosis. Though limited studies have been conducted for molecular diagnosis, there are no established serologic tests for this highly fatal infection. OBJECTIVE: To develop and evaluate an indirect in-house enzyme-linked immunosorbent assay (ELISA) utilising antigens of Rhizopus arrhizus for detecting anti-Rhizopus antibodies (IgG and IgM) in sera of patients with mucormycosis. METHODS: We extracted both secretory and mycelial Rhizopus antigens using standardised protocols. Bradford assay was used for protein quantification. We then standardised an indirect ELISA using R. arrhizus mycelial and secretory antigens (10.0 µg/mL in bicarbonate buffer pH 9.2) for detecting anti-Rhizopus IgG and IgM antibodies in patient sera. We included patients with mucormycosis, other fungal infections, and healthy controls. Antibody index value (E-value) was calculated for each patient sample. RESULTS: Asparagine broth culture filtrate utilising 85% ammonium sulphate salt fractionation and mycelial homogenate grown in yeast extract peptone dextrose (YPD) broth precipitated with trichloroacetic acid (TCA) yielded a large amount of good-quality protein for the assay. We included 55 patients with mucormycosis (rhino-orbito-cerebral mucormycosis [ROCM, n = 39], pulmonary [n = 15], gastrointestinal [n = 1]), 24 with other fungal infections (probable aspergillosis [n = 14], candidiasis [n = 10]), and healthy controls (n = 16). The sensitivity of the antibody test for diagnosing mucormycosis ranged from 83.6-92.7% for IgG and 72.7-87.3% for IgM, with a specificity of 91.7-92.5% for IgG and 80-82.5% for IgM. The sera from patients with other fungal infections and healthy individuals did not show significant cross-reactivity. CONCLUSION: The detection of anti-Rhizopus IgG antibody performed significantly better in comparison to IgM-based ELISA for diagnosing both ROCM (sensitivity of 84.6% vs. 69.2%) and pulmonary cases (86.6% vs. 80.0%). More extensive studies are required to confirm our findings.
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Anticorpos Antifúngicos , Antígenos de Fungos , Ensaio de Imunoadsorção Enzimática , Imunoglobulina G , Imunoglobulina M , Mucormicose , Rhizopus , Sensibilidade e Especificidade , Testes Sorológicos , Mucormicose/diagnóstico , Mucormicose/microbiologia , Mucormicose/imunologia , Humanos , Rhizopus/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Antígenos de Fungos/imunologia , Antígenos de Fungos/análise , Testes Sorológicos/métodos , Anticorpos Antifúngicos/sangue , Imunoglobulina M/sangue , Imunoglobulina G/sangue , Feminino , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Mechanisms behind multiple organ involvement in lupus, is still an enigma for researchers. Mitochondrial dysfunction and oxidative stress are known to be important aspects in lupus etiology however, their role in lupus organ manifestation is yet to be understood. The present study is based on the understanding of interplay between AMPK/PGC-1α/SIRT-1 axis, mitochondrial complexes, and anti-oxidants levels, which might be involved in lupus organ pathology. METHODOLOGY: Pristane-induced Balb/c mice lupus model (PIL) was utilised and evaluation of anti-oxidants, mitochondrial complexes, pro-inflammatory cytokines levels, biochemical parameters were performed by standard procedures. Tissues were studied by haematoxylin and eosin staining followed by immunohistochemistry. The AMPK/PGC-1α/SIRT-1 expression was analysed by using qPCR and flowcytometry. Analysis of reactive oxygen species (ROS) among WBCs was performed by using various dyes (DCFDA, Mitosox, JC-1) on flowcytometry. RESULT: Significant presence of immune complexes (Tissue sections), ANA (Serum), and pro-inflammatory cytokines (plasma), diminished anti-oxidants and altered biochemical parameters depict the altered pathology in PIL which was accompanied by dysregulated mitochondrial complex activity. Differential expression of the AMPK/PGC-1α/SIRT-1 axis was detected in tissue and correlation with mitochondrial and antioxidant activity emerged as negative in PIL group while positive in controls. Close association was observed between ROS, mitochondrial membrane potential, and AMPK/PGC-1α/SIRT-1 axis in WBCs. CONCLUSION: This study concludes that mitochondria play a dual role in lupus organ pathology, contributing to organ damage while also potentially protecting against damage through the regulation of interactions between antioxidants and the AMPK axis expression.
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Purpose: To compare the quality of complete dentures and quality of life of participants rehabilitated by using TENS (Transcutaneous electric nerve stimulation) facilitated impression making with manual impressions. Material and methods: Ten completely edentulous participants were enrolled in the crossover, pilot study. Participants were randomized in 2 groups. Five participants in each group were rehabilitated by dentures fabricated with TENS facilitated definitive impression technique (group T) and conventional impression technique (group C). In group T, Bioelectric border molding was done for the participants, that uses electric stimulation of the nerves supplying the muscles. In group C, incremental border molding using modeling plastic impression compound was carried out. Participants in each group used the dentures for 3 months. After 3 months, OHIP-EDENT questionnaire responses were obtained from the participants to observe the oral health related quality of life. A dental specialist recorded denture quality by Kapur scoring criteria. After one month wash period, the treatment was swapped between the groups. OHIP-EDENT scores and Kapur score were recorded for the alternate dentures after 3 months of use. Descriptive analysis was followed by Mann Whitney test to compare the overall scores between group T and group C for OHIP-EDENT, the scores for individual domains of OHIP-EDENT, and Kapur score for denture evaluation (α = 0.05). Results: The overall OHIP-EDENT scores within each domain were less in group T when compared with the scores in group C and Kapur score for group T was more than group C. The difference was statistically significant i.e. P = 0.002 & 0.003 respectively. Conclusions: Less OHIP-EDENT scores in group T imply better perception of quality of life of individuals due to better performance of stomatognathic system. The higher Kapur scores in group T signifies better quality of dentures when TENS was used for definitive impression making.
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Background and aim: A new concept of antibiotic sterilization has come into existence which can be used to sterilize the demineralized portion of the teeth with minimal or ultraconservative excavation of caries in deep dentinal carious lesions as an alternative for indirect pulp therapy (IPT) and pulpotomy to avoid further complications. This study was undertaken to compare the success rates of antibiotic sterilization, indirect pulp treatment, and pulpotomy in the management of primary teeth with deep carious lesion. Materials and methods: Ninety teeth involving deep carious lesions approaching pulp in primary molars were selected and randomly divided into three groups containing 30 teeth. Group I was treated with antibiotic sterilization using 3Mix-MP paste, group II was treated with indirect pulp treatment using calcium hydroxide, and group III was treated with conventional pulpotomy using 15.5% ferric sulfate (FS) solution. Clinical and radiographic analysis of all three groups was performed at 1, 3, 6, 9, and 12 months to evaluate the success of treatment procedures using predetermined criteria. Pearson's Chi-squared test and McNemar test were used for statistical analysis. Results: At the end of the 12-month follow-up period, the overall clinical and radiographic success was determined to be 96.3% for group I, 100% for group II, and 96.4% for group III. There were no statistically significant differences observed between the success of three groups, suggesting that either of the procedures can be adopted for the management of deep carious lesions approaching pulp in primary teeth. Conclusion: Antibiotic sterilization can be introduced as a newer modality in the management of deep carious lesions approaching pulp in primary teeth which is ultraconservative in nature and reduces the risk of pulp exposure in comparison with indirect pulp treatment and pulpotomy procedures. How to cite this article: Saxena D, Garg N, Pathivada L, et al. Success Rates of Antibiotic Sterilization, Indirect Pulp Treatment, and Pulpotomy in the Management of Primary Teeth with Deep Carious Lesions. Int J Clin Pediatr Dent 2024;17(3):237-242.
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OBJECTIVE: There is a lack of evidence on the effectiveness of antidotes in the management of organophosphate and carbamate (OPC) poisoning. We aimed to review the efficacy and safety of glycopyrrolate in the management of OPC poisoning. METHODOLOGY: Databases such as PubMed, Scopus, Embase, and Cochrane Library were extensively searched from inception to November 2022 and updated till October 2023. Interventional, observational, and descriptive studies assessing the efficacy and safety of glycopyrrolate administered in any dose, route, and duration for the management of OPC poisoning published in the English language were considered for this review. The treatment with any other regimen that did not include glycopyrrolate was regarded as the comparator. The survival, intensive care unit (ICU) days and ventilatory outcomes were considered efficacy outcomes, and adverse effects were considered safety outcomes. Suitable quality assessment tools were used to assess the risk of bias in the included studies. Two independent reviewers were involved in the study selection, data extraction, and quality assessment and any discrepancies were resolved through mutual discussion or consultation with a third reviewer. RESULTS: A total of 9 studies (2 RCTs, 4 cohorts, 1 case series, and 2 case reports) out of 591 nonduplicate records were considered for this review. Overall, the RCTs were observed to have a moderate quality, and observational studies and descriptive studies were found to have good quality. All the included studies used atropine administration as a standard treatment option along with glycopyrrolate. The OPC patients treated with glycopyrrolate had a fewer hospitalization days with comparable recovery and ventilatory outcomes than those that had not been treated with glycopyrrolate. The occurrence of adverse events and complications was lower in the glycopyrrolate group than in the control group. CONCLUSION: Currently, there is a lack of comparative studies to recommend the use of glycopyrrolate in OPC poisoning, and further interventional studies are required to make an evidencebased recommendation on this topic.
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Cerebral phaeohyphomycosis (CP) stands as an exceedingly uncommon yet severe type of fungal infection affecting the central nervous system, attributable to dematiaceous fungi. Despite the patient's immune status, CP is associated with grave prognosis. In the present study, authors describe the first case of left thalamic fungal abscess due to Rhinocladiella mackenziei in an immunocompetent 39-year-old male patient in Jaipur, Rajasthan. Early diagnosis by direct microscopy of aspirated pus and extensive management with surgical excision and prolonged antifungal coverage showed favourable outcome. The present case is one of the few cases documented globally who has survived.
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Antifúngicos , Abscesso Encefálico , Humanos , Masculino , Adulto , Abscesso Encefálico/microbiologia , Abscesso Encefálico/diagnóstico , Abscesso Encefálico/tratamento farmacológico , Antifúngicos/uso terapêutico , Feoifomicose Cerebral/diagnóstico , Feoifomicose Cerebral/microbiologia , Índia , Tálamo/patologia , Tálamo/microbiologia , Tálamo/diagnóstico por imagem , Resultado do TratamentoRESUMO
Basal cell carcinoma (BCC) is the most common skin cancer. Skin cancers may present either as a non-invasive tumor or an invasive malignancy. The terminology of carcinoma in situ is used when the tumor is either just limited to epidermis or not present as single cells or nests in the dermis. However, currently the terminology superficial BCC is inappropriately used instead of BCC in situ when the skin cancer is limited to epidermis. In this study we compare the pathologic changes of superficial, nodular, and infiltrative BCCs using electron microscopy to identify the ultrastructural characteristics and validate the previously proposed terminology. Three cases of BCC (superficial BCC, nodular BCC, and infiltrative BCC) diagnosed by dermatopathologists at our institute were selected for review. Paraffin block tissues from these cases were sent for electron microscopy studies which demonstrated disruption of basal lamina in both nodular and infiltrative type of BCC, while it remains intact in BCC superficial type after extensive examination. Therefore, similar to other in situ skin cancers, there is no invasion of the neoplasm in superficial BCC into the dermis. Hence, the older term superficial BCC should be appropriately replaced with the newer terminology BCC in situ.
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Xeroderma pigmentosum is a rare autosomal recessive disorder resulting in heightened cutaneous photosensitivity due to aberrant DNA repair mechanisms. Early-life developmental delay and cognitive impairment have been described in xeroderma pigmentosum cases. However, psychiatric symptoms in adulthood as the presenting feature of xeroderma pigmentosum have not been reported. We report a young adult with xeroderma pigmentosum group G presenting with prominent neuropsychiatric manifestations and evidence of neurodegeneration. The clinical, laboratory, and radiological findings, skin biopsy, and the results of the genetic testing of the patient have been described after obtaining written and informed consent. A young adult male with skin photosensitivity since infancy developed hyper-religiosity, delusions, suicidal ideations, speech hypernasality, lower limb spasticity, and cognitive impairment over the past four years. The MRI of the brain showed diffuse cerebral atrophy. The skin biopsy from bilateral cheeks showed evidence of flattening and thinning of rete ridges, pigment incontinence, and perivascular and periappendageal inflammatory infiltrate. The whole exome sequencing in ethylenediaminetetraacetic acid (EDTA) blood revealed a compound heterozygous likely pathogenic mutation in intron 13 (c.2880-2A>G (3' splice site)) and a mutation in exon 15 (c.3146del (p.Asp1049ValfsTer12)) in the ERCC5 gene suggestive of xeroderma pigmentosum group G. This case highlights that prominent neuropsychiatric features in adulthood can occur due to xeroderma pigmentosum. Thus, xeroderma pigmentosum group G should be considered as a possibility among young adults presenting with neuropsychiatric features, evidence of neurodegeneration, and early-life skin photosensitivity.
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Multidrug-resistant yeast Candida auris is a serious threat to public health with documented survival in various hospital niches. The dynamics of this survival benefit and its trade off with drug resistance are still unknown for this pathogen. In this study we investigate the oxidative stress response (OSR) in fluconazole-resistant C. auris and compare its relative fitness with fluconazole-susceptible strains. A total of 351 C. auris clinical isolates (61 fluconazole-susceptible and 290 fluconazole-resistant) were screened for stress tolerance by spot assay and 95.08 % fluconazole-susceptible isolates were hyper-resistant to oxidative stress while majority (94.5 %) fluconazole-resistant isolates had lower oxidative tolerance. Expression of Hog1 and Cta1 gene transcript levels and cellular catalase levels were significantly higher in fluconazole-susceptible isolates and a corresponding higher intracellular reactive oxygen species level (iROS) was accumulated in the fluconazole-resistant isolates. Biofilm formation and cell viability under oxidative stress revealed higher biofilm formation and better viability in fluconazole-susceptible isolates. Fluconazole-resistant isolates had higher basal cell wall chitin. On comparison of virulence, the % cytotoxicity in A549 cell line was higher in fluconazole-susceptible isolates and the median survival of the infected larvae in G. mellonella infection model was higher in fluconazole-resistant (5; IQR:4.5-5 days) vs. fluconazole-susceptible C. auris (2; IQR:1.5-2.5 days). All organisms evolve with changes in their environmental conditions, to ensure an optimal balance between proliferation and survival. Development of tolerance to a certain kind of stress example antifungal exposure in yeast can leads to a compensatory decrease in tolerance for other stresses. This study provides useful insights into the comparative fitness and antifungal susceptibility trade off in C. auris. We report a negative association between H2O2 tolerance and fluconazole susceptibility. Using in-vitro cell cytotoxicity and in-vivo survival assays we also demonstrate the higher virulence potential of fluconazole-susceptible C. auris isolates corroborating the negative correlation between susceptibility and pathogen survival or virulence. These findings could also be translated to clinical practice by investigating the possibility of using molecules targeting stress response and fitness regulating pathways for management of this serious infection.
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Mucormycosis is an emerging disease primarily affecting the immunocompromised host, but scarce evidence is available for solid organ transplant recipients (SOTRs). We systematically reviewed 183 cases occurring in SOTRs, exploring epidemiology, clinical characteristics, causative pathogens, therapeutic approaches, and outcomes. Kidney transplants accounted for half of the cases, followed by heart (18.6%), liver (16.9%), and lung (10.4%). Diagnosis showed a dichotomous distribution, with 63.7% of cases reported within 100 days of transplantation and 20.6% occurring at least 1 year after transplant. The 90-day and 1-year mortality rates were 36.3% and 63.4%, respectively. Disseminated disease had the highest mortality at both time points (75% and 93%). Treatment with >3 immunosuppressive drugs showed a significant impact on 90-day mortality (odds ratio [OR], 2.33; 95% CI, 1.02-5.66; P = .0493), as did a disseminated disease manifestation (OR, 8.23; 95% CI, 2.20-36.71; P = .0027) and the presence of diabetes (OR, 2.35; 95% CI, 1.01-5.65; P = .0497). Notably, prophylaxis was administered to 12 cases with amphotericin B. Further investigations are needed to validate these findings and to evaluate the potential implementation of prophylactic regimens in SOTRs at high risk.
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Liver abscess is a potentially life-threatening medical emergency. Prompt empirical antimicrobial with or without percutaneous aspiration or drainage is therapeutic. The rational for using empirical intravenous broad-spectrum antimicrobials upfront instead of oral Fluoroquinolone or Cephalosporin is contentious. In this double blind randomized control clinical trial 69 participants received Ciprofloxacin (500 mg q 12 hourly) and 71 participants received Cefixime (200 mg q 12 hourly) orally for 2 weeks. Both the group received oral Metronidazole (800 mg q 8 hourly) for 2 weeks and percutaneous drainage or aspiration of the abscess was done as per indication and followed-up for 8 weeks. Out of 140 participants, 89.3% (N = 125) achieved clinical cure, 59 (85.5%) in Ciprofloxacin group and 66 (93%) in Cefixime group (p = 0.154). Mean duration of antimicrobial therapy was 16.2 ± 4.3 days, 15.1 ± 4.5 days in Ciprofloxacin group and 16.0 ± 4.2 days in Cefixime group (p = 0.223). Total 15 (10.7%) participants had treatment failure, 10 (14.5%) in Ciprofloxacin group and 5 (7.0%) in Cefixime group (p = 0.154). The most common reason for treatment failure was need of prolong (> 4 weeks) antimicrobial therapy due to persistent hepatic collection requiring drainage, which was significantly (p = 0.036) higher in Ciprofloxacin (14.5%, N = 10) group, compared to the Cefixime (4.2%, N = 3) group. In conclusion, both, the Ciprofloxacin or Cefixime plus Metronidazole for duration of 2-3 weeks were efficacious as empirical oral antimicrobial regimen along with prompt percutaneous drainage or aspiration for the treatment of uncomplicated liver abscess with similar efficacy. Oral Cefixime was better than Ciprofloxacin in term of lesser chance of treatment failure due to persistent collection which is required to be investigated further in larger clinical trial.Trial registration: clinicaltrials.gov PRS ID: NCT03969758, 31/05/2019.
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Antibacterianos , Cefixima , Ciprofloxacina , Abscesso Hepático , Metronidazol , Humanos , Ciprofloxacina/administração & dosagem , Ciprofloxacina/uso terapêutico , Metronidazol/administração & dosagem , Metronidazol/uso terapêutico , Cefixima/uso terapêutico , Cefixima/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Abscesso Hepático/tratamento farmacológico , Abscesso Hepático/microbiologia , Resultado do Tratamento , Método Duplo-Cego , Quimioterapia Combinada , Drenagem , IdosoRESUMO
During surge of COVID-19-associated mucormycosis (CAM), we identified five cases of CAM where two different species of Mucorales were isolated. All had history of diabetes mellitus and presented with clinical features suggesting rhino-orbital mucormycosis. The patients grew different species from their nasal scraping/biopsy samples, Rhizopus arrhizus, R. homothallicus (n = 2); R. homothallicus, Lictheimia corymbifera (n = 1); R. arrhizus, Mucor spp (n = 1); and L. corymbifera, Apophysomyces variabilis (n = 1). All patients underwent surgical and medical (liposomal amphotericin B) treatment. All, except one growing A. variabilis and L. corymbifera survived. Mixed infection by more than one Mucorales in CAM is unique and warrants epidemiological investigation.
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COVID-19 , Mucorales , Mucormicose , Mucormicose/diagnóstico , Mucormicose/microbiologia , Humanos , Mucorales/isolamento & purificação , Mucorales/classificação , Masculino , Pessoa de Meia-Idade , COVID-19/complicações , Feminino , Antifúngicos/uso terapêutico , Anfotericina B/uso terapêutico , Adulto , SARS-CoV-2 , IdosoRESUMO
Background: Mucormycosis is a fungal infection that can affect multiple organs. The role of fine-needle aspiration cytology (FNAC) in its diagnosis is not well documented. Aim: The objective of this study was to describe the detailed cytomorphologic features of mucormycosis on FNAC samples. Materials and Methods: A retrospective analysis of all cases diagnosed as mucormycosis on FNAC between January 2014 and July 2021 was performed for detailed cytomorphological evaluation and correlation to clinical data and microbiological studies wherever available. FNA was computed tomography-guided (n = 38), ultrasonography-guided (n = 31) or palpation-guided (n = 12), and slides were reviewed in two cases. Results: A total of 83 cases of mucormycosis were evaluated. An immunocompromised setting was observed in 48 cases. The most common site of FNA was the lung (n = 57) followed by liver, soft tissue, palate, mediastinum, orbital/ocular region, and lymph node. Isolated renal involvement, a unique feature, was seen in seven cases. The aspirates were necrotic to pus-like or blood-mixed particulate. Broad, nonseptate, foldable, ribbon-like fungal hyphae showing right-angled branching were seen. The tissue reaction was predominantly necro-inflammatory (n = 36), bland necrotic (n = 22), mixed inflammatory (n = 16), suppurative (n = 5), necrotizing granulomatous (n = 3), and granulomatous (n = 1). Immunocompromised patients showed mixed inflammatory responses more frequently. Fungal culture was positive for Rhizopus species in 2/13 cases and molecular testing in two additional cases corresponding to Rhizopus and Syncephalastrum spp. Conclusion: FNA provides quick and conclusive diagnosis of mucormycosis from varied anatomic sites enabling prompt institution of therapy. The tissue response is variable and to some extent dependent on the immune status of the patient.
RESUMO
Breast cancer is the most common cancer among women. Currently, it poses a significant threat to the healthcare system due to the emerging resistance and toxicity of available drug candidates in clinical practice, thus generating an urgent need for the development of new potent and safer anti-breast cancer drug candidates. Coumarin (chromone-2-one) is an elite ring system widely distributed among natural products and possesses a broad range of pharmacological properties. The unique distribution and pharmacological efficacy of coumarins attract natural product hunters, resulting in the identification of numerous natural coumarins from different natural sources in the last three decades, especially those with anti-breast cancer properties. Inspired by this, numerous synthetic derivatives based on coumarins have been developed by medicinal chemists all around the globe, showing promising anti-breast cancer efficacy. This review is primarily focused on the development of coumarin-inspired anti-breast cancer agents in the last three decades, especially highlighting design strategies, mechanistic insights, and their structure-activity relationship. Natural coumarins having anti-breast cancer efficacy are also briefly highlighted. This review will act as a guideline for researchers and medicinal chemists in designing optimum coumarin-based potent and safer anti-breast cancer agents.
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Crohn's disease (CD) is a complex chronic inflammatory disorder with both gastrointestinal and extra-intestinal manifestations associated immune dysregulation. Analyzing 202,359 cells from 170 specimens across 83 patients, we identify a distinct epithelial cell type in both terminal ileum and ascending colon (hereon as 'LND') with high expression of LCN2, NOS2, and DUOX2 and genes related to antimicrobial response and immunoregulation. LND cells, confirmed by in-situ RNA and protein imaging, are rare in non-IBD controls but expand in active CD, and actively interact with immune cells and specifically express IBD/CD susceptibility genes, suggesting a possible function in CD immunopathogenesis. Furthermore, we discover early and late LND subpopulations with different origins and developmental potential. A higher ratio of late-to-early LND cells correlates with better response to anti-TNF treatment. Our findings thus suggest a potential pathogenic role for LND cells in both Crohn's ileitis and colitis.
Assuntos
Colo , Doença de Crohn , Oxidases Duais , Células Epiteliais , Íleo , Lipocalina-2 , Doença de Crohn/patologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Humanos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Colo/patologia , Íleo/patologia , Lipocalina-2/metabolismo , Lipocalina-2/genética , Oxidases Duais/genética , Oxidases Duais/metabolismo , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Feminino , Adulto , Fator de Necrose Tumoral alfa/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Pessoa de Meia-IdadeRESUMO
Introduction: The purpose of the study was to evaluate and compare the levels of salivary Interleukin-6 (IL-6) before and after the placement of dental implants in patients who are supplemented with nitric oxide (NO). Materials and Methods: The study comprised 34 patients, divided into control and study groups (17 in each group). The control group was given a placebo and in the study group, nitric oxide supplement was prescribed, whereas the control group received a placebo. Saliva samples were taken before placement of dental implants, first and third day after the implant placement. The levels of salivary IL-6 were assessed using an enzyme-linked immunosorbent assay test. Results: Statistical analysis showed a significant P value (<0.05) with respect to IL-6 levels on first and third days after placement of dental implants. Salivary IL-6 levels in the study group declined significantly. On day three, the IL-6 values for the control and study groups were 0.0639 and 0.0443, respectively. Within the groups, it was observed that there was a significant decrease in IL-6 values from day one to day three. Discussion: The levels of salivary IL-6 reduced from day one to day three more significantly and consistently in patients prescribed with NO supplements post-dental implant placement, suggesting better resolution of inflammation.