Pharmacokinetic Analysis of Gatifloxacin and Dexamethasone in Rabbit Ocular Biofluid Using a Sensitive and Selective LC-MS/MS Method.

Bacterial keratitis (BK) is an infection that causes inflammation of the cornea and, if severe, can result in blindness. Topical fluoroquinolones combined with corticosteroids have been shown to be useful in the treatment of BK. A rapid, selective, and sensitive bioanalytical method for simultaneous quantification of Gatifloxacin (GAT) and Dexamethasone (DEX) has been developed and validated using tandem mass spectrometry (LC-MS/MS). Optimal separation was accomplished in under 5 min using an Agilent Zorbax C18 column (100 mm × 4.6 mm, 3.5 µm). The mobile phase was composed of a blend of 0.2% formic acid in triple distilled water and methanol with a flow rate of 0.65 mL/min in isocratic mode. GAT and DEX were detected in positive electrospray ionization multiple reaction monitoring mode (MRM), and the retention time was found to be at 1.64 and 2.93 min, respectively. The linearity of GAT and DEX was found to be in the range of 1.56-400 ng mL-1 with good precision and accuracy. The method was validated according to USFDA regulatory guidelines. The validated method was effectively utilized for preclinical pharmacokinetic analysis of GAT and DEX in rabbit tear fluid following the topical application of a commercial formulation.

Axial ligand-induced high electrocatalytic hydrogen evolution activity of molecular cobaloximes in homo- and heterogeneous medium.

Three new molecular cobaloxime complexes with the general formula [ClCo(dpgH)2L] (1-3), where L1 = N-(4-pyridylmethyl)-1,8-naphthalimide, L2 = 4-bromo-N-(4-pyridylmethyl)-1,8-naphthalimide, L3 = 4-piperidin-N-(4-pyridylmethyl)-1,8-naphthalimide, have been synthesized and characterized by UV-Vis, multinuclear NMR, FT-IR and PXRD spectroscopic techniques. The crystal structures of all complexes have also been reported. The electrocatalytic activity of complexes is investigated under two catalysis conditions: (i) homogeneous conditions in acetonitrile using acetic acid (AcOH) as a proton source and (ii) heterogeneous conditions upon immobilization onto the surface of activated carbon cloth (CC). Complex 3 exhibited high electrocatalytic HER activity under both homogeneous and heterogeneous conditions. It catalyses proton reduction to molecular hydrogen in acetonitrile solution at a lower overpotential (640 mV) with a high turnover frequency (TOF) of 524.57 s-1 and demonstrates good stability in acidic conditions. Furthermore, catalytic (working) electrodes are prepared by immobilizing the complexes onto the surface of activated carbon cloth (CC) for electrocatalytic HER under heterogeneous conditions. An impressive HER performance was again obtained with catalytic electrode 3@CC in 1.0 M KOH, achieving a current density of -10 mA cm-2 at an overpotential of 262 mV. Chronoamperometric (CA) studies showed no significant decay of the initial current density for 10 h, indicating the excellent stability of 3@CC. Additionally, UV-Vis and NMR spectral studies of the recovered catalyst after electrocatalysis revealed no structural changes, demonstrating its robustness under reaction conditions.

Deciphering the iron enigma: Navigating the complexities of iron metabolism in critical illness.

Iron is a double-edged sword! Despite being essential for numerous physiological processes of the body, a dysregulated iron metabolism can result in tissue damage, exaggerated inflammatory response, and increased susceptibility to infection with certain pathogens that thrive in iron-rich environment. During sepsis, there is an alteration of iron metabolism, leading to increased transport and uptake into cells. This increase in labile iron may cause oxidative damage and cellular injury (ferroptosis) which progresses as the disease worsens. Critically ill patients are often complicated with systemic inflammation which may contribute to multiple organ dysfunction syndrome or sepsis, a common cause of mortality in intensive care unit. Originally, ferritin was known to play an important role in the hematopoietic system for its iron storage capacity. Recently, its role has emerged as a predictor of poor prognosis in chronic inflammation and critical illnesses. Apart from predicting the disease outcome, serum ferritin can potentially reflect disease activity as well.

Comparison of clinical and patient-reported outcomes in patients with benign euthyroid solitary nodules after ultrasound-guided percutaneous microwave ablation and endoscopic thyroidectomy.

BACKGROUND: Percutaneous ultrasound-guided microwave ablation (MWA) for benign solid thyroid nodules is the newest modality for treatment. However, the differences in treatment outcomes between MWA and endoscopic thyroidectomy vestibular approach (TOETVA) for patients with benign euthyroid solitary nodules remain unknown. We are sharing initial results from our prospective study. METHODS: Prospective study between January 2022 and December 2023 was conducted and data were noted at 3 time points in patients planned for treatment (Preoperative, 1 week, and 12 months). Main outcome measures were clinical outcome and comparison of thyroid-related quality of life using the ThyPRO-39hin and swallowing-related quality of life using the SWAL-QoL. RESULTS: Of the 36 included patients, 20 patients underwent TOETVA and 16 underwent MWA. Both the groups were comparable in terms of demographic and clinicopathological profiles. The nodule volume reduction rate of patients at 12 months after MWA was 75.10% and 100% for TOETVA. The mean preoperative ThyPRO-39hin and SWAL-QoL scores were comparable in all domains between the two groups. Mean ThyPRO-39hin and SWAL-QoL scores on postoperative day 7 were significantly better in the MWA group in domains impaired social life (p < 0.0001) and impaired daily life (p = 0.0002). However, at the end of 12 months, mean ThyPRO-39hin and SWAL-QoL scores became significantly better in the TOETVA group as compared to the MWA group. CONCLUSION: Our findings suggest that transoral endoscopic thyroidectomy results in significant superior clinical outcome, thyroid-related quality of life, and swallowing-related quality of life in the long term.

Characteristics of Bilateral Adrenal Lesions: Experience from an Indian Tertiary Care Centre.

Introduction: The aetiologies in unilateral and bilateral adrenal lesions can be different with different clinical implications and management guidelines, the latter having aetiologies like hyperplasia, infections, infiltrative lesions and neoplasia. Bilateral tumours are more likely to have hereditary/syndromic associations. There is limited data on the clinical and pathological profile of bilateral adrenal lesions. Methods: This was a retrospective study where patients with bilateral adrenal lesions were selected from a total of 266 patients with adrenal lesions who presented to our institute between January 2016 and August 2022. The demographic, laboratory and imaging data were retrieved from the Hospital Information System and patient case files. Results: The study included 51 patients; the mean age at presentation was 51.15 years (range 14 to 82 years). Forty-eight patients (94.1%) were symptomatic at presentation with an average duration of symptoms being 10.68 months (range 10 days to 1 year). The most common presentation was adrenal insufficiency in 18 cases (38%), followed by fever in 17 cases (36%). The commonest aetiology, as revealed on histopathology, was histoplasmosis (n = 22, 43%), followed by pheochromocytoma (n = 11, 21.5%), metastases (n = 6, 11.7%), adrenal hyperplasia (n = 5, 9.8%), adrenocortical adenoma (n = 1, 1.9%), lymphoma (n = 3, 5.8%), neuroblastoma (n = 1, 1.9%), myelolipoma (n = 1, 1.9%) and tuberculosis (n = 1, 1.9%). Histoplasmosis and metastatic lesions were commonly seen in older people, and pheochromocytoma was associated with young age. 6/11 patients with a diagnosis of bilateral pheochromocytoma were associated with family history, genetic mutation and extra-adrenal involvement. Conclusion: The approach to bilateral adrenal lesions differs from that of unilateral lesions due to differences in aetiologies and the more significant role of genetics in some bilateral tumours. The age at presentation, presenting symptoms, lesion size and biochemical features help delineate varied underlying aetiologies.

Racial Disparities in Treatment and Outcomes of Pediatric Hepatoblastoma.

Pediatric Hepatoblastoma is a rare malignancy of the liver. This study used the National Cancer Database (NCDB) to identify 1068 patients diagnosed with hepatoblastoma from 2004 to 2020. χ 2 and Analysis of Variance testing, as well as Kaplan-Meier, Cox Regression, and multinomial logistic regression models were used. Data was analyzed using SPSS version 27, and statistical significance was set at α=0.05. Our results found Black patients experienced a significantly lower median survival rate compared with White patients, a difference which persisted after controlling for covariates. Black patients were also less likely to receive surgery and chemotherapy and more likely to be from low-income households than White patients. White patients had a significantly shorter inpatient hospital stay compared to Black patients and were more likely to receive treatment at more than 1 CoC accredited facility. There was no significant difference in grade, size of tumor, metastasis, or time of diagnosis to surgery. This study showed Black patients experienced inferior overall survival when diagnosed and treated for hepatoblastoma compared to White patients.

Etiopathology, Epidemiology, Diagnosis, and Treatment of Fungal Keratitis.

Fungal keratitis (FK) is a severe ocular condition resulting from corneal infection that is prevalent in tropical countries, particularly in developing regions of Asia and Africa. Factors like corneal lens misuse, inappropriate steroid use, and diagnostic challenges have provoked the epidemic. FK causes significant vision impairment, scarring, and ocular deformities. Accurate pathological diagnosis is crucial for effective therapeutic intervention. Topical antifungal therapy with surface healing medications proves effective in preventing fungal-borne ulcers. Managing FK requires a comprehensive understanding of fungal pathogenesis, guiding formulation strategies and preventive measures to curb global ocular blindness. This review provides in-depth insights into FK, covering etiology, epidemiology, pathogenesis, therapeutic interventions, antifungal resistance, limitations, prevention, and future perspectives on ocular surface disease management.

Optimizing Drug Combinations for T-PLL: Restoring DNA Damage and P53-Mediated Apoptotic Responses.

T-prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm associated with marked chemotherapy resistance and continued poor clinical outcomes. Current treatments, i.e. the CD52-antibody alemtuzumab, offer transient responses, with relapses being almost inevitable without consolidating allogeneic transplantation. Recent more detailed concepts of T-PLL's pathobiology fostered the identification of actionable vulnerabilities: (i) altered epigenetics, (ii) defective DNA damage responses, (iii) aberrant cell-cycle regulation, and (iv) deregulated pro-survival pathways, including TCR and JAK/STAT signaling. To further develop related pre-clinical therapeutic concepts, we studied inhibitors of (H)DACs, BCL2, CDK, MDM2, and clas-sical cytostatics, utilizing (a) single-agent and combinatorial compound testing in 20 well-characterized and molecularly-profiled primary T-PLL (validated by additional 42 cases), and (b) 2 independent murine models (syngeneic transplants and patient-derived xenografts). Overall, the most efficient/selective single-agents and combinations (in vitro and in mice) in-cluded Cladribine, Romidepsin ((H)DAC), Venetoclax (BCL2), and/or Idasanutlin (MDM2). Cladribine sensitivity correlated with expression of its target RRM2. T-PLL cells revealed low overall apoptotic priming with heterogeneous dependencies on BCL2 proteins. In additional 38 T-cell leukemia/lymphoma lines, TP53 mutations were associated with resistance towards MDM2 inhibitors. P53 of T-PLL cells, predominantly in wild-type configuration, was amenable to MDM2 inhibition, which increased its MDM2-unbound fraction. This facilitated P53 activa-tion and down-stream signals (including enhanced accessibility of target-gene chromatin re-gions), in particular synergy with insults by Cladribine. Our data emphasize the therapeutic potential of pharmacologic strategies to reinstate P53-mediated apoptotic responses. The identified efficacies and their synergies provide an informative background on compound and patient selection for trial designs in T-PLL.

Incidence and Prognostic Significance of Androgen Receptors (AR) in Indian Triple-Negative Breast Cancer (TNBC).

Molecular sub-characterization of triple-negative breast cancer (TNBC) has great therapeutic and possibly prognostic implications. The primary aim of this study was to investigate the incidence of luminal androgen receptor (LAR) subtype of TNBC and secondary aims were sub-categorization and clinico-pathologic correlation of LAR breast cancers. Retrospective study (January 2008 and 31st of December 2018) consisting of 157 TNBC patients. Androgen receptor (AR) expression was measured by immunohistochemical analysis. One percent cutoff was set as a positive expression. Sub-categorization was done on the basis of EGFR (> 15% of tumor cells) and Ki-67 expression (low- < 11%, intermediate- 11-20%, and high- > 21%). AR expression was correlated with various clinico-pathologic features and outcomes of the patients. The incidence of AR expression in TNBC was 24.8%. Considering different thresholds of > 5%, > 10%, and > 20% immunostaining, the incidence of AR positivity was 18.4, 15.2, and 11.5% respectively. The incidence of Ki-67 (p = 0.89) and EGFR (p = 0.643) expression did not differ significantly in AR-positive and -negative TNBC. Based on EGFR expression 19, 67 and 14% patients were categorized as low, intermediate, and high risk respectively. Low-risk (p ≤ 0.001) and low-grade (p = 0.014) tumors were more likely to have > 10% AR expression. Clinico-pathological profile, response to neoadjuvant chemotherapy, disease-free survival (p = 0.458), and overall survival (p = 0.806) did not significantly differ between AR expressing and negative TNBC. On multivariate analysis, only tumor staging was a significant predictor of survival (p = 0.012) and AR expression of > 10% revealed a trend towards improved survival (p = 0.07). When considering only AR-positive TNBC, AR expression of > 10% (p = 0.038), distant metastases (p = 0.003), and EGFR status (p = 0.024) were significantly associated with survival. AR expression does not seem to very strongly correlate with prognosis in TNBC and further studies could focus more on its predictive role in deciding anti-androgen therapy.

Nanoemulsion Carriers for Ocular Fungal Infection: Main Emphasis on Keratomycosis.

Keratomycosis, also termed fungal keratitis (FK), is an invasive eye condition for which there is a lack of available effective treatment due to pharmacological shortages and vital ocular obstacles. This severe corneal infection typically suppurates and eventually ulcerates, ultimately causing blindness or decreased vision. According to epidemiological studies, FK is more common in warm, humid places with an agricultural economy. The use of nanoemulsion carriers for ocular fungal infection has been promoting better treatment and patient compliance. The persistent fungal infection like FK, affecting particularly the stroma heralds complications thereby posing difficulty in diagnosis and treatment. To help treat refractory cases and improve outcomes, recently targeted drug delivery techniques and novel antifungal drugs shall be explored. A delay in diagnosis may cause corneal fungal infections to have irreversible consequences, which cannot be avoided. However, infections can develop into ocular perforation even after receiving intense care. The commonly used chemotherapy for FK is based on topical (natamycin 5% is typically first-line therapy) and systemic administration of azole drugs. To address the problems related to better treatment, various nanoemulsion carriers were discussed. Novel drug delivery systems based on nanoemulsions are a viable therapeutic option for treating keratomycosis and may be a candidate method for overcoming obstacles in the treatment of many other ocular illnesses when combined with different hydrophobic medicines. With a brief explanation of the pathogenesis, this article seeks to give readers a thorough analysis of current trends, various treatment choices, and care strategies for fungal keratitis.

Codetermination of antimicrobial agents in rabbit tear fluid using LC-MS/MS assay: Insights into ocular pharmacokinetic study.

Managing ocular microbial infections typically requires pharmacotherapy using antibiotic eye drops, such as moxifloxacin hydrochloride (MFX), combined with an antifungal agent like amphotericin B (AB). We carried out and validated an LC-MS/MS assay to quantify these compounds in rabbit tear fluid in order to look into the pharmacokinetics of these two drugs. We employed a protein precipitation technique for the extraction of drugs under examination. A Waters Symmetry C18 column was used to separate the analytes and internal standard. The composition of the mobile phase was like (A) 0.1% v/v formic acid in water and (B) methanol. The detection of MFX and AB was accomplished through the utilization of positive ion electrospray ionization under multiple reaction monitoring mode. The linearity curves for both analytes exhibited an acceptable trendline across a concentration range of 2.34-300 ng/mL for MFX and 7.81-1000 ng/mL for AB in surrogate rabbit tear fluid. The lower limit of quantitation for MFX was 2.34 ng/mL, while for AB, it was 7.81 ng/mL. The approach was strictly validated, encompassing tests of selectivity, linearity (with r2 > 0.99), precision, accuracy, matrix effects, and stability. Consequently, we employed this method to evaluate the pharmacokinetics profiles of MFX and AB in rabbit tear fluid following single topical doses.

Polymers and their engineered analogues for ocular drug delivery: Enhancing therapeutic precision.

Ocular drug delivery is constrained by anatomical and physiological barriers, necessitating innovative solutions for effective therapy. Natural polymers like hyaluronic acid, chitosan, and gelatin, alongside synthetic counterparts such as PLGA and PEG, have gained prominence for their biocompatibility and controlled release profiles. Recent strides in polymer conjugation strategies have enabled targeted delivery through ligand integration, facilitating tissue specificity and cellular uptake. This versatility accommodates combined drug delivery, addressing diverse anterior (e.g., glaucoma, dry eye) and posterior segment (e.g., macular degeneration, diabetic retinopathy) afflictions. The review encompasses an in-depth exploration of each natural and synthetic polymer, detailing their individual advantages and disadvantages for ocular drug delivery. By transcending ocular barriers and refining therapeutic precision, these innovations promise to reshape the management of anterior and posterior segment eye diseases.

XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53-p21 and p27 pathways.

Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in CTCL cells. KPT-330 reduces cell proliferation, induces G1 cell cycle arrest and apoptosis. RNA-sequencing was used to explore the underlying mechanisms. Genes associated with the cell cycle and the p53 pathway were significantly enriched with KPT-330 treatment. KPT-330 suppressed XPO1 expression, upregulated p53, p21WAF1/Cip1, and p27Kip1 and their nuclear localization, and downregulated anti-apoptotic protein (Survivin). The in vivo efficacy of KPT-330 was investigated using a bioluminescent xenograft mouse model of CTCL. KPT-330 blocked tumor growth and prolonged survival (p < 0.0002) compared to controls. These findings support investigating the use of KPT-330 and next-generation XPO1 inhibitors in CTCL.

Comparison of indocyanine green angiography vs intraoperative parathyroid hormone in early prediction of risk of post-thyroidectomy hypocalcemia: a prospective cohort study.

Introduction: Indocyanine green (ICG) angiography is the 'real-time intraoperative imaging' technique used to reduce the chances of hypoparathyroidism in post-thyroidectomy patients. In our study, the authors predicted the risk of early post-thyroidectomy hypocalcemia by intraoperative evaluation of parathyroid gland perfusion by ICG angiography. Materials and methods: In patients who underwent total thyroidectomy, ICG angiography was done using the SPY PHI imaging system (Stryker). Post-thyroid specimen removal, scoring of parathyroids was done in spy contrast mode. All 4 or <4 visualized parathyroids were scored for vascularity with the highest score of 8. Serum ionized calcium was done 6 h postsurgery and on the morning and evening of postoperative days 1 and 2. Calcium supplements were given to only those who developed clinical or severe biochemical hypocalcemia. Results: Out of 60, postoperative hypocalcemia was noted in 41 patients. Total ICG score ≤5 was seen in 34 patients, out of which 28 developed postoperative hypocalcemia showing PPV 82.3% and diagnostic accuracy of 68.3% while iPTH (4.28 pmol/l) showed PPV 76.7 and diagnostic accuracy 70 %. In eight patients, none of the glands was scored as 2 (White) and all these patients developed hypocalcemia requiring calcium infusion. Conclusion: The absence of visualization of at least 1 well-perfused (score 2) gland on ICG angiography is highly predictive of hypocalcemia and the majority of patients with total ICG score ≤5 developed hypocalcemia in the immediate postoperative period. ICG is a good predictor of the absence of hypoparathyroidism after thyroidectomy and is comparable to iPTH in the prediction of post-thyroidectomy hypocalcemia.

Pirfenidone: A Promising Drug in Ocular Therapeutics.

Pirfenidone, initially indicated for lung fibrosis, has gone beyond its original purpose, and shown promise in eye care. This detailed review tracks its evolution from lung treatment to aiding eye healing as evidenced by published literature. Pirfenidone's multifaceted attributes extend to mitigating corneal fibrosis, inflammation, and trauma. Through rigorous investigations, its efficacy emerges in diabetic retinopathy, macular degeneration, and postoperative glaucoma interventions. As an unheralded protagonist, pirfenidone reshapes ocular care paradigms, inviting renewed research opportunities.