Immune Checkpoint Inhibitors and Endocrine Disruption: A Case of Hyponatremia and Adrenal Insufficiency.

Immune checkpoint inhibitors, such as pembrolizumab, have transformed cancer therapy by enhancing the immune system's ability to combat tumors, but they can also lead to immune-related adverse events, including adrenal insufficiency. This case report presents a 52-year-old male with a history of malignant melanoma who developed adrenal insufficiency after four months of pembrolizumab therapy. The patient was admitted with symptoms of malaise, vomiting, abdominal pain, and poor appetite. Laboratory tests revealed significant metabolic abnormalities including hyponatremia, hypokalemia, and elevated thyroid-stimulating hormone. Further endocrine evaluation confirmed the diagnosis of secondary adrenal insufficiency, likely due to pembrolizumab-induced inflammation of the pituitary gland. The patient was treated with corticosteroid replacement therapy, leading to clinical improvement, and pembrolizumab was discontinued due to the risk of worsening adrenal insufficiency. This case underscores the importance of early recognition and management of adrenal insufficiency in patients receiving pembrolizumab. While the exact cause of pembrolizumab-induced adrenal insufficiency is not fully understood, it may involve an autoimmune attack on cells in the pituitary gland. Prompt identification and treatment are essential to prevent potentially life-threatening complications, and this case highlights the need for clinicians to maintain a high level of awareness for adrenal insufficiency in patients presenting with nonspecific symptoms during or after immunotherapy.

Comparing the efficacy of multiple quantitative and qualitative ultrasound parameters for the diagnosis of carpal tunnel syndrome.

PURPOSE: Carpal tunnel syndrome (CTS) is a compression neuropathy causing significant morbidity. Over the years, ultrasound has been evaluated as an alternative to nerve conduction study (NCS) for diagnosing CTS, however, there is no consensus as to which ultrasound parameter is the best. Our study aimed to determine and compare the efficacy of various ultrasound-based variables for diagnosis of CTS. METHODS: 80 patients with clinical suspicion of CTS underwent ultrasound examination with calculation of cross-sectional area (CSA), delta CSA, wrist forearm ratio (WFR), palmer bowing (PB), flattening ratio (FR), flexor retinaculum thickness (FT), and evaluation of echogenicity and vascularity of median nerve. NCS was taken as the gold standard and the diagnostic efficacy of all these variables was compared, followed by receiver operator curve (ROC) analysis. RESULTS: Delta CSA had the highest accuracy (91.25%), followed by CSAc (80%), WFR (78.75%), and PB (73.75%). Youden's index and sensitivity were highest for delta CSA (0.783 and 96.15% respectively), while specificity was highest for FT (89.29%). The highest area under the curve was noted for delta CSA (97.1%), followed by WFR (AUC = 87.4%) and CSAc (AUC = 86.0%). CONCLUSION: Delta CSA was found to be the best ultrasound parameter for diagnosis of CTS, followed by CSAc, WFR, and PB, and can be used as an alternative to NCS. Using ROC analysis this study also predicted the best cut-off values for these parameters which could improve their diagnostic accuracy and further research is needed to confirm these findings.

Identification of a novel cryptic variant chromosomal rearrangement involving 9q34, 22q11.2, and 5q22 resulting in ins(9;22) and t(5;22) in chronic myeloid leukemia: a case report.

Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic stem cells characterized by the aberrant production and uncontrolled proliferation of mature granulocytes with normal cell differentiation. The Philadelphia (Ph) chromosome resulting from reciprocal translocation between chromosomes 9 and 22 is the main genetic molecular hallmark of CML seen in more than 90% of the patients. However, about 5-10% of CML patients show a variant genetic rearrangement, involving one or more chromosomes in addition to 9 and 22. Herein, we describe the results of hematological, cytogenetic, fluorescence in situ hybridization (FISH), and high-end molecular analysis in a 77-year-old man diagnosed with CML. The combination of conventional cytogenetic analysis along with metaphase FISH and whole chromosomal paint revealed a novel cryptic variant chromosomal rearrangement involving 9q34, 22q11.2, and 5q22, resulting in ins(9;22) and t(5;22). At the molecular level, using PCR, myeloid NGS panels, and whole transcriptome analyses, we showed that this complex rearrangement indeed resulted in the formation of the BCR::ABL1 e13a2 major fusion transcript. No additional somatic mutations or kinase domain mutations were identified, thereby suggesting that the current case is indeed genetically homogeneous. This study provided strong evidence to support the idea that insertion-derived BCR::ABL1 fusions often involve complex chromosomal abnormalities that are overlooked by conventional cytogenetics but can be identified by a combination of conventional, molecular cytogenetics, and high-end NGS studies.

Tear film parameters and meibography in eyes of children with vernal keratoconjunctivitis.

PURPOSE: To study tear film parameters and Meibomian glands in pediatric patients with vernal keratoconjunctivitis (VKC). METHODS: Forty-four eyes of 22 patients with VKC and 44 eyes of 22 age-matched controls were studied in a hospital-based cross-sectional study. Each subject underwent a complete ophthalmological examination including slit-lamp biomicroscopy, non-invasive break-up time (NIBUT), fluorescein break-up time (FBUT), corneal fluorescein staining, and Schirmer's test. Non-contact meibography was performed using a Sirius topographer. RESULTS: All patients had VKC grades between 1 and 3 (Bonini scale). The mean NIBUT for cases was 8.83 ± 4.02 s and in controls, it was 15 ± 2.8 s (P value < 0.001). The mean FBUT for cases was 9.41 ± 3.45 s and in controls, it was 16.7 ± 2.5 s (P value < 0.001). Schirmer's values were 32 ± 3.1 mm in cases and 21.4 ± 4.1 mm in controls, which were significantly higher (P value < 0.001). Also, 22.72% of the cases had corneal fluorescein staining in the form of superficial punctuate keratitis, whereas none of the control groups showed corneal staining. The examination of Meibomian glands using non-contact meibography showed a mean Meibomian gland dropout in the upper lid to be 29.7 ± 14.4% in VKC cases and 10.5 ± 3.2% in controls (P value < 0.001). Meibography of the lower lid showed 25.9 ± 10.2% dropout in cases and 20.5 ± 6.1% in controls (P value = 0.004). CONCLUSION: Tear film parameters were significantly deranged in children with VKC in the active stage as compared to age-matched controls. Children with VKC also had a higher Meibomian gland dropout.

From Smoothies to Dialysis: The Impact of Oxalate Nephropathy.

Oxalate nephropathy is a rare cause of acute kidney injury that can lead to end-stage renal disease. This case report describes a 54-year-old male with type 2 diabetes mellitus and chronic kidney disease who presented for a routine clinic follow-up. Laboratory tests revealed significant deterioration in renal function with an unrevealing history and symptoms suggestive of the process. Initial investigations for worsening renal function were inconclusive, prompting a renal biopsy that confirmed acute tubular injury with abundant calcium oxalate deposits. Further investigation into dietary history revealed that the patient regularly consumed high-oxalate foods, such as spinach and kale smoothies, under the impression they were beneficial for his diabetes. Despite the initiation of hemodialysis, the patient did not recover renal function and remains dialysis-dependent. This case underscores the need for a high index of suspicion for oxalate nephropathy in chronic kidney disease patients presenting with unexplained acute kidney injury. Diagnosis is confirmed through renal biopsy and should be considered in patients with relevant dietary histories.

Diagnosis of an unusual orbital abscess following sub-Tenon's steroid injection: a case report.

Orbital abscesses are caused by infection within or near the orbit and show obvious signs of pain, proptosis and raised inflammatory markers. Diagnosis is based on clinical features and radiological imaging, and requires early antibiotics and often surgical drainage to save vision. Sub-Tenon's injections of triamcinolone acetonide (TA) have caused localized infections in previous reports, which have responded to therapeutic interventions. Here we report a case where a delayed presentation of an orbital abscess secondary to sub-Tenon's TA for persistent post-operative cystoid macular oedema, without obvious signs of infection, rapidly progressed to cause orbital compartment syndrome. Despite treatment, the patient lost complete vision in the affected eye. This case discusses the rare and unusual cause of abscess formation and a diagnostic dilemma.

Mesenchymal Wnts are required for morphogenetic movements of calvarial osteoblasts during apical expansion.

Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral to calvarial growth and enclosure of the brain. The cellular behaviors and signals underlying the morphogenetic process of calvarial expansion are unknown. Time-lapse light-sheet imaging of mouse embryos revealed calvarial progenitors intercalate in 3D in the CM above the eye, and exhibit protrusive and crawling activity more apically. CM cells express non-canonical Wnt/planar cell polarity (PCP) core components and calvarial osteoblasts are bidirectionally polarized. We found non-canonical ligand Wnt5a-/- mutants have less dynamic cell rearrangements and protrusive activity. Loss of CM-restricted Wntless (CM-Wls), a gene required for secretion of all Wnt ligands, led to diminished apical expansion of Osx+ calvarial osteoblasts in the frontal bone primordia in a non-cell autonomous manner without perturbing proliferation or survival. Calvarial osteoblast polarization, progressive cell elongation and enrichment for actin along the baso-apical axis were dependent on CM-Wnts. Thus, CM-Wnts regulate cellular behaviors during calvarial morphogenesis for efficient apical expansion of calvarial osteoblasts. These findings also offer potential insights into the etiologies of calvarial dysplasias.

Apical expansion of calvarial osteoblasts and suture patency is dependent on fibronectin cues.

The skull roof, or calvaria, is comprised of interlocking plates of bones that encase the brain. Separating these bones are fibrous sutures that permit growth. Currently, we do not understand the instructions for directional growth of the calvaria, a process which is error-prone and can lead to skeletal deficiencies or premature suture fusion (craniosynostosis, CS). Here, we identify graded expression of fibronectin (FN1) in the mouse embryonic cranial mesenchyme (CM) that precedes the apical expansion of calvaria. Conditional deletion of Fn1 or Wasl leads to diminished frontal bone expansion by altering cell shape and focal actin enrichment, respectively, suggesting defective migration of calvarial progenitors. Interestingly, Fn1 mutants have premature fusion of coronal sutures. Consistently, syndromic forms of CS in humans exhibit dysregulated FN1 expression, and we also find FN1 expression altered in a mouse CS model of Apert syndrome. These data support a model of FN1 as a directional substrate for calvarial osteoblast migration that may be a common mechanism underlying many cranial disorders of disparate genetic etiologies.

Synergistically engineered nanotransethosomes for co-delivery of methotrexate and baicalin for enhanced transdermal delivery against rheumatoid arthritis: formulation, characterisation and in vivo pharmacodynamic evaluation.

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease that significantly impacts the quality of life of those affected. Owing to the complex pathophysiology of RA, it is not possible for any singular treatment to entirely impede the progression of the disease. Hence, the current study aimed to adopt a holistic and synergistic approach towards the management of RA by means of a co-delivery strategy involving methotrexate (MTH), a conventional slow-acting anti-rheumatic drug, and baicalin (BCN), a bioactive phytochemical using a transethosomal (TRS) gel formulation.Purpose: The present study aims to evaluate the potential benefits of administering MTH and BCN in nanoparticulate form, which may lead to improved stability and solubility, as well as enhanced penetration into the arthritic tissues of interest.Methods and results: The MTH-BCN-TRS that were synthesised exhibited small particle size of 151.3 nm and polydispersity index of 0.125, as well as a favourable zeta potential of -32.22 mV. Additional assessments were conducted, including a pharmacokinetic analysis, TEM, skin permeation analysis and confocal microscopy. According to the Confocal laser scanning microscopy (CLSM) study, the formulated MTH-BCN-TRS gel exhibited superior MTH and BCN permeation through the skin layers when compared to the MTH-BCN suspension gel. The MTT experiment on Raw 264.7 and SW982 cell lines revealed a considerable reduction (p < .05) in the IC50 value of the MTH-BCN-TRS formulation (9.2 mM and 43.2 mM, respectively) in comparison to the drug suspension. According to the findings of the in vivo study, it was found that the MTH-BCN-TRS gel exhibits significantly promising anti-arthritic properties when compared to the conventional diclofenac gel. This was demonstrated through histopathological studies and radiographic analysis. Furthermore, skin irritation investigation on Wistar albino rats confirmed that the formulated MTH-BCN-TRS is a safe option for topical treatment on the skin. The present study has confirmed that the formulated TRS vesicles are a valuable carrier for the transdermal delivery of MTH and BCN, which may be used for the management of rheumatoid arthritis.

Nose to brain delivery of naringin loaded transniosomes for epilepsy: formulation, characterisation, blood-brain distribution and invivo pharmacodynamic evaluation.

The current work limns the preparation of naringin-loaded transnioosomes (NRN-TN) to enhance NRN solubility, permeation and bioavailability via nasal mucosa for intranasal delivery. NRN-TN was created by the thin-film hydration technique, and with the BBD (Box-Behnken design), optimisation was carried out. NRN-TNopt was characterised for the vesicle size, PDI (Polydispersity index), zeta potential, entrapment efficiency (EE) and in vitro NRN release. For further assessment, nasal permeation study, study of Blood-brain distribution, TEM (Transmission Electron Microscopy), and CLSM (Confocal Scanning Laser Microscopy) were conducted withal. The NRN-TNopt exhibited spherical as well as sealed vesicles with a considerable small size of 151.3 nm, an EE of 75.23 percent, a PDI of 0.1257, and an in vitro release of 83.32 percent. CLSM investigation revealed that the new formulation allows for higher NRN permeation across nasal mucosa than the NRN solution. The blood-brain distribution investigation revealed that intranasally administered NRN-TN had a greater Cmax and AUC0-24 h than orally administered NRN-TN. Seizure activity and neuromuscular coordination as measured by the rotarod test, biochemical estimate of oxidative stress indicators, and histological investigations demonstrated that the NRN-TN has superior anti-epileptic potential in comparison to the standard diazepam. In addition, nasal toxicity studies demonstrate that the NRN-TN formulation is safer for intranasal administration. This study confirmed that the created TN vesicle formulation is a valuable carrier for the intranasal administration of NRN for the treatment of epilepsy.

Mesenchymal Wnts are required for morphogenetic movements of calvarial osteoblasts during apical expansion.

Apical expansion of calvarial osteoblast progenitors from the cranial mesenchyme (CM) above the eye is integral for calvarial growth and enclosure of the brain. The cellular behaviors and signals underlying the morphogenetic process of calvarial expansion are unknown. During apical expansion, we found that mouse calvarial primordia have consistent cellular proliferation, density, and survival with complex tissue scale deformations, raising the possibility that morphogenetic movements underlie expansion. Time lapse light sheet imaging of mouse embryos revealed that calvarial progenitors intercalate in 3D to converge supraorbital arch mesenchyme mediolaterally and extend it apically. In contrast, progenitors located further apically exhibited protrusive and crawling activity. CM cells express non-canonical Wnt/Planar Cell Polarity (PCP) core components and calvarial osteoblasts are bidirectionally polarized. We found non-canonical ligand, Wnt5a-/- mutants have less dynamic cell rearrangements, protrusive activity, and a flattened head shape. Loss of cranial mesenchyme-restricted Wntless (CM-Wls), a gene required for secretion of all Wnt ligands, led to diminished apical expansion of OSX+ calvarial osteoblasts in the frontal bone primordia in a non-cell autonomous manner without perturbing proliferation or survival. Calvarial osteoblast polarization, progressive cell elongation and enrichment for actin cytoskeleton protein along the baso-apical axis were dependent on CM-Wnts. Thus, CM-Wnts regulate cellular behaviors during calvarial morphogenesis and provide tissue level cues for efficient apical expansion of calvarial osteoblasts. These findings also offer potential insights into the etiologies of calvarial dysplasias.

Clinicopathologic Spectrum of Lysozyme-Associated Nephropathy.

Introduction: Lysozyme-associated nephropathy (LyN), a rare cause of kidney injury in patients with chronic myelomonocytic leukemia (CMML), has not been well described to date. We report the clinicopathologic spectrum of LyN from a multi-institutional series. Method: We identified 37 native kidney biopsies with LyN and retrospectively obtained clinicopathologic data. Results: Thirty-seven patients had a median age of 74 years and included 78% males. Their most common presentation was acute kidney injury (AKI) or AKI on chronic kidney disease (CKD) (66%) with median estimated glomerular filtration rate (eGFR) of 21.7 ml/min per 1.73 m2, and proteinuria of 1.7 g. A minority (15%) had partial Fanconi syndrome. Serum lysozyme levels were elevated in all tested. Hematologic disorder (n = 28, 76%) was the most common etiology, including CMML (n = 15), acute myeloid leukemia (n = 5), and myelodysplastic syndrome (MDS) (n = 5). Nonhematologic causes (n = 5, 14%), included metastatic neuroendocrine carcinoma (n = 3), sarcoidosis, and leprosy. Etiology was unknown in 4 (11%). Pathology showed proximal tubulopathy with abundant hypereosinophilic intracytoplasmic inclusions, with characteristic staining pattern by lysozyme immunostain. Mortality was high (8/30). However, among the 22 alive, including 85% treated, 7 had improved kidney function, including 1 who discontinued dialysis and 6 with increase in eGFR >15 ml/min per 1.73 m2 compared with eGFR at the time of biopsy. Conclusion: Increased awareness of the full clinicopathologic spectrum of LyN may lead to prompt diagnosis, earlier treatment, and potentially improved outcome of this rare entity.

Functional characterization of novel mutations in the conserved region of EPSPS for herbicide resistance in pigeonpea: structure-based coherent design.

Prospectively, agroecosystems for the growth of crops provide the potential fertile, productive, and tropical environment which attracts infestation by weedy plant species that compete with the primary crop plants. Infestation by weed is a major biotic stress factor faced by pigeonpea that hampers the productivity of the crop. In the modern era with the development of chemicals the problem of weed infestation is dealt with armours called herbicides. The most widely utilized, post-emergent, broad-spectrum herbicide has an essential active ingredient called glyphosate. Glyphosate mechanistically inhibits a chloroplastic enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) by competitively interacting with the PEP binding site which hinders the shikimate pathway and the production of essential aromatic amino acids (Phe, Tyr, Trp) and other secondary metabolites in plants. Moreover, herbicide spray for weed management is lethal to both the primary crop and the weeds. Therefore, it is critical to develop herbicide-resistant crops for field purposes to reduce the associated yield and economic losses. In this study, the in-silico analysis drove the selection and validation of the point mutations in the conserved region of the EPSPS gene, which confers efficient herbicide resistance to mutated-CcEPSPS enzyme along with the retention of the normal enzyme function. An optimized in-silico validation of the target mutation before the development of the genome-edited resistant plant lines is a prerequisite for testing their efficacy as a proof of concept. We validated the combination of GATIPS mutation for its no-cost effect at the enzyme level via molecular dynamic (MD) simulation.Communicated by Ramaswamy H. Sarma.

HIGHLIGHTSWeed infestation is a major biotic stress factor and a consistent problem in agriculture.Development of glyphosate-resistant mutation is crucial to minimize the yield loss in agriculturally or nutritionally important crops for field application.Present in-silico approach is a proof-of-concept for validation of the selected glyphosate-resistant mutations.The current study has validated the combination of GATIPS mutation for its glyphosate-resistant phenotype and no negative cost effect at the enzyme simulation level.

Structural, morphological, and optical characteristics of Gd2 Si2 O7 :Dy3+ nanophosphors for WLEDs.

Yellowish-white light-emitting Gd2-x Si2 O7 :xDy3+ (x = 1-5 mol%) nanophosphors were prepared using a solution combustion synthesis method. Fluorescence spectrophotometry and X-ray diffraction measurements were performed to scrutinize the optical performances and phase recognition of the designated nanophosphors. The outcomes specified that the prepared phosphors were crystallized into a triclinic phase with a P-1 space group. As the concentration of Dy3+ ions was increased, the unit-cell volume decrease proportionally due to the replacement of large-sized Gd3+ by small-sized Dy3+ ions. Under ultraviolet excitation at 349 nm, emission spectra consisted of two pronounced emission lines at ~482 nm (blue line), ~578 nm (yellow line), and a relatively weaker emission at ~670 nm (red line) due to 4 F9/2 →6 H15/2 , 4 F9/2 →6 H13/2 , and 4 F9/2 →6 H11/2 intraconfigurational transitions of Dy3+ ions, respectively. The evidence about the site symmetry around Dy3+ ions was examined by considering the ratio of yellow-to-blue emission intensity. The observed critical distance (Rc ) value was ~20.56 Å (≫5 Å), which signified that energy transfer primarily occurred due to multipolar interaction. The obtained coordinates were close to the white region of the Commission Internationale de l'Éclairage chromaticity diagram, which marked a significant milestone in the development of white light-emitting diodes.

Linalool-Incorporated Synergistically Engineered Modified Liposomal Nanocarriers for Enhanced Transungual Delivery of Terbinafine against Onychomycosis.

This work investigates the synthesis of linalool-containing invasomes for terbinafine (TBF-IN) in order to increase the solubility, bioavailability, and nail permeability of terbinafine (TBF) for transungual administration. TBF-IN was created utilising the thin-film hydration technique, and with the Box-Behnken design (BBD), optimisation was carried out. TBF-INopt were investigated for vesicle size, zeta potential, PDI (Polydispersity index), entrapment efficiency (EE) and in vitro TBF release. In addition, nail permeation analysis, TEM (transmission electron microscopy), and CLSM (confocal scanning laser microscopy) were performed for further evaluation. The TBF-INopt exhibited spherical as well as sealed vesicles with a considerably small size of 146.3 nm, an EE of 74.23 per cent, a PDI of 0.1612, and an in vitro release of 85.32 per cent. The CLSM investigation revealed that the new formulation had better TBF nail penetration than the TBF suspension gel. The antifungal investigation demonstrated that the TBF-IN gel has superior antifungal activity against Trichophyton rubrum and Candida albicans compared to the commercially available terbinafine gel. In addition, an investigation of skin irritation using Wistar albino rats indicates that the TBF-IN formulation is safe for topical treatment. This study confirmed that the invasomal vesicle formulation is an effective vehicle for the transungual delivery of TBF for the treatment of onychomycosis.