Imatinib- and Nilotinib-Induced Lichenoid Eruption in Chronic Myeloid Leukemia: A Rare Case Report.

Imatinib and nilotinib are inhibitors of tyrosine kinases (TKIs) generated from the bcr-abl fusion protein, c-Kit, and platelet-derived growth factor receptors. Cutaneous adverse effects (AEs) of TKI are the most frequent non-hematological sequelae. In our case, the common molecular target raises the possibility that cross-intolerance, in which similar AEs occur with both agents, can arise. We hereby report a rare case report on cross-intolerance of cutaneous AEs of imatinib and nilotinib in chronic myeloid leukemia.

Improving Access to Eye Care in Rural Communities: PocDoc's Web-Based Visual Acuity Screening Tool.

Objective: Visual acuity (VA) testing is crucial for early intervention in cases of visual impairment, especially in rural health care. This study aimed to determine the potential of a web-based VA test (PocDoc) in addressing the unique health care needs of rural areas through the comparison in its effectiveness against the conventional VA test in identifying visual impairment among an Indian rural population. Methods: Prospective comparative study conducted in December 2022 at a tertiary referral eye care center in central India. We evaluated all patients with the PocDoc VA tests using three device types, and the conventional VA test. Bland-Altman plot (BAP) compared PocDoc and conventional VA tests. Fisher's exact tests evaluated associations between categorical parameters. Kruskal-Wallis tests followed by post hoc Dunn's tests identified association between categorical parameters and numerical parameters. Results: We evaluated 428 patients (792 measurements of VA) with mean age 36.7 (±23.3) years. PocDoc resulted in slightly worse VA scores (mean logMAR: 0.345) than conventional (mean logMAR: 0.315). Correlation coefficient between the conventional and PocDoc logMAR VA values was rho = 0.845 and rho2 = 0.7133 (p = 6.617 × 10-215; adjusted p = 2.205 × 10-214). Most data points fell within the interchangeable range of ±0.32 on BAP. Difference between the two methods increased with higher logMAR values, indicating poorer agreement for worse VA scores. Conclusions: Identifying and addressing the unique health care needs of rural populations is critical, including access to appropriate and effective VA testing methods. Validating and improving VA testing methods can ensure early intervention and improve the quality of life for individuals with visual impairment.

Identifying Selectivity Filters in Protein Biosensor for Ligand Screening.

Specialized sensing mechanisms in bacteria enable the identification of cognate ligands with remarkable selectivity in highly xenobiotic-polluted environments where these ligands are utilized as energy sources. Here, via integrating all-atom computer simulation, biochemical assay, and isothermal titration calorimetry measurements, we determine the molecular basis of MopR, a phenol biosensor's complex selection process of ligand entry. Our results reveal a set of strategically placed selectivity filters along the ligand entry pathway of MopR. These filters act as checkpoints, screening diverse aromatic ligands at the protein surface based on their chemical features and sizes. Ligands meeting specific criteria are allowed to enter the sensing site in an orientation-dependent manner. Sequence and structural analyses demonstrate the conservation of this ligand entry mechanism across the sensor class, with individual amino acids along the selectivity filter path playing a critical role in ligand selection. Together, this investigation highlights the importance of interactions with the ligand entry pathway, in addition to interactions within the binding pocket, in achieving ligand selectivity in biological sensing. The findings enhance our understanding of ligand selectivity in bacterial phenol biosensors and provide insights for rational expansion of the biosensor repertoire, particularly for the biotechnologically relevant class of aromatic pollutants.

IMMEDIATE VITRECTOMY vs TAP AND INJECT IN EYES WITH ACUTE POSTCATARACT ENDOPHTHALMITIS AND VISUAL ACUITY ≥HM: A Randomized Clinical Trial.

PURPOSE: To compare the outcomes of immediate pars plana vitrectomy (PPV) and tap and inject in eyes with postcataract surgery endophthalmitis. METHODS: Patients presenting with acute postcataract surgery endophthalmitis and visual acuity between ≥ hand movement and <6/18 were randomized to receive either PPV (Group A) or tap and inject (Group B). RESULTS: There were 26 and 31 eyes in Group A and Group B, respectively. The final mean visual acuity at 6 weeks [0.14 (Snellen equivalent 6/7.5) versus 0.22 (Snellen equivalent 6/9.5) LogMAR in Groups A and B, respectively; P = 0.2] was similar. However, eyes in Group A had significantly greater mean letter gain in vision compared with Group B (66.36 vs. 43.36, P = 0.02), and more eyes in Group A (88%) than in Group B (65%) attained a visual acuity of ≥ 6/18 ( P = 0.06). Eyes in Group B needed more reinterventions including delayed vitrectomy after tap and inject than those in Group A (39% vs. 8%; P = 0.09). On subgroup analysis, the mean visual acuity at the final follow-up was significantly better in the immediate PPV group compared with the delayed PPV group ( P = 0.04). CONCLUSION: PPV resulted in earlier recovery, lesser interventions, and greater change in visual acuity than tap and inject in eyes with postcataract surgery endophthalmitis presenting with visual acuity of ≥HM.

Disseminated Tuberculosis Presenting as Ciliary Body and Thyroid Mass Lesions: A Case Report.

PURPOSE: To report a case of disseminated TB presenting as ciliary body and thyroid mass lesions. CASE REPORT: A 17-year-old male patient presented with a thyroid mass and blurring of vision in the left eye. A diagnosis of ciliary body granuloma was made. Although the Mantoux was negative, the HRCT chest showed evidence of miliary TB, and the fine needle aspiration cytology from the thyroid mass revealed AFB. On initiation of Antitubercular therapy(ATT), a paradoxical worsening of ciliary body granuloma was noted which resolved on starting steroids. CONCLUSION: Involvement of thyroid gland and ciliary body although rare in tuberculosis, may be the presenting feature of disseminated TB. Paradoxical reactions seen after initiation of ATT in these cases may respond well to oral steroids.

Macular Necrotizing Retinitis as a Presenting Feature of Atypical Fulminant SSPE: A Case Report.

Purpose: To report ocular findings in a case of atypical fulminant SSPECase report: A 20-year-old male who came with macular necrotising retinitis in both his eyes in absence of any neurological feature. Within a week the patient developed dystonic posturing and seizures. CSF examination revealed raised measles antibody titres and EEG was suggestive of SSPE. The patient succumbed to the disease within 35 days of presentation.Conclusion: SSPE can rarely have a rapidly progressive downhill course without typical neurological features and ophthalmic features which appear to be more consistent may help in clinching the diagnosis in these cases.

Choroidal Involvement in a Case of Acute Retinal Necrosis.

PURPOSE: To report choroidal involvement in a case of ARN. CASE REPORT: A 26-year-old immunocompetent female presented with a history of decreased vision in the right eye for 4 days. The best corrected visual acuity in the right eye was 3/60. Anterior segment examination showed circumciliary congestion, endothelial pigments, and 1+ cells in the anterior chamber. Fundus examination revealed mild vitritis, disc edema, multifocal patchy retinitis lesions involving the fovea and mid periphery, and arteriolitis. OCT revealed an RPE bump at the macula corroborating with hypocyanacent lesions on indocyanine angiography, which persisted till the late phase, indicating choroidal involvement. The patient was started on oral valacyclovir and oral steroids. Additionally, intravitreal ganciclovir injection was added, leading to a favorable outcome. The final visual acuity post silicone oil removal was 6/60. CONCLUSION: This is a unique case of ARN having choroidal involvement along with the previously described classical features.

Endogenous Endophthalmitis - A Major Review.

Endogenous endophthalmitis (EE) is an uncommon but potentially devastating ocular infection involving the inner layers of the eye. The global incidence of EE is on the rise. Common ocular signs and symptoms associated with EE include conjunctival injection, ocular pain, and reduced visual acuity. On clinical examination, a history of prior or coexisting systemic infections, symptoms (e.g., fever, malaise), and localizing features may be noted. Clinical diagnosis is often challenging, resulting in critical delays that contribute to a poor prognosis. Blood cultures and ocular fluid samples can aid in conforming causative pathogen(s), after which empirical antibiotic therapy, both systemic and intravitreal, should be instated. The use of steroids to suppress inflammation remains controversial. Surgical options include pars plana vitrectomy. Overall prognosis varies depending on host and pathogen factors, and early diagnosis and initiation of appropriate treatment are crucial.

Phenol sensing in nature is modulated via a conformational switch governed by dynamic allostery.

The NtrC family of proteins senses external stimuli and accordingly stimulates stress and virulence pathways via activation of associated σ54-dependent RNA polymerases. However, the structural determinants that mediate this activation are not well understood. Here, we establish using computational, structural, biochemical, and biophysical studies that MopR, an NtrC protein, harbors a dynamic bidirectional electrostatic network that connects the phenol pocket to two distal regions, namely the "G-hinge" and the "allosteric linker." While the G-hinge influences the entry of phenol into the pocket, the allosteric linker passes the signal to the downstream ATPase domain. We show that phenol binding induces a rewiring of the electrostatic connections by eliciting dynamic allostery and demonstrates that perturbation of the core relay residues results in a complete loss of ATPase stimulation. Furthermore, we found a mutation of the G-hinge, ∼20 Å from the phenol pocket, promotes altered flexibility by shifting the pattern of conformational states accessed, leading to a protein with 7-fold enhanced phenol binding ability and enhanced transcriptional activation. Finally, we conducted a global analysis that illustrates that dynamic allostery-driven conserved community networks are universal and evolutionarily conserved across species. Taken together, these results provide insights into the mechanisms of dynamic allostery-mediated conformational changes in NtrC sensor proteins.

Prevalence, Severity, and Treatment Outcomes of Meibomian Gland Dysfunction in Patients With Dry Eye Symptoms at a Tertiary Care Center in South India.

Background and objective Dry eye disease (DED) is one of the most common reasons why patients seek eye care. With increasing age, widespread adoption of technology, and environmental changes, its prevalence has been on the rise, and will likely increase further. Meibomian gland dysfunction (MGD) is the most common cause of DED; however, for a variety of reasons, it is currently underrecognized. We aimed to determine the etiology of DED from a sample of patients visiting our center with dry eye symptoms and study the characteristics of those diagnosed with MGD. Methodology We conducted this prospective observational study from 2016 to 2018. We included patients with two or more dry eye symptoms and excluded those with systemic conditions or structural issues causing dry eye. Each patient underwent a detailed evaluation of the dry eye, including the Ocular Surface Disease Index (OSDI) questionnaire, Oxford corneal staining, Schirmer test 1, tear film break-up time (TBUT), tear meniscus height, and non-contact meibography. All patients subsequently received appropriate treatment. Patients with MGD were evaluated once again after one month. Results We included 250 patients in the study. Their mean (standard deviation) age was 45.3 (16.9) years, and 138 (55%) of them were males. Grittiness and itching were the most common symptoms. MGD was the most common diagnosis, seen in 100 (40%), followed by chronic allergic conjunctivitis. Patients with MGD were more likely to be elderly and had significantly worse DED parameters. Over half of all MGD cases were mild or less severe. With appropriate treatment, all DED metrics improved significantly. Conclusions MGD was the most common cause of DED in our sample. Patients with MGD were more likely to be elderly and had more severe DED, consistent with other studies in the literature. With specific treatment of MGD, there was a significant improvement in the patients' condition. DED is a growing ocular health issue that causes great detriment to patients' quality of life and finances. Our findings support the need for a detailed evaluation and specific treatment of patients presenting with dry eye symptoms.

Cooperativity in ATP Hydrolysis by MopR Is Modulated by Its Signal Reception Domain and by Its Protein and Phenol Concentrations.

The NtrC family of AAA+ proteins are bacterial transcriptional regulators that control σ54-dependent RNA polymerase transcription under certain stressful conditions. MopR, which is a member of this family, is responsive to phenol and stimulates its degradation. Biochemical studies to understand the role of ATP and phenol in oligomerization and allosteric regulation, which are described here, show that MopR undergoes concentration-dependent oligomerization in which dimers assemble into functional hexamers. The oligomerization occurs in a nucleation-dependent manner with a tetrameric intermediate. Additionally, phenol binding is shown to be responsible for shifting MopR's equilibrium from a repressed state (high affinity toward ATP) to a functionally active, derepressed state with low-affinity for ATP. Based on these findings, we propose a model for allosteric regulation of MopR. IMPORTANCE The NtrC family of bacterial transcriptional regulators are enzymes with a modular architecture that harbor a signal sensing domain followed by a AAA+ domain. MopR, a NtrC family member, responds to phenol and activates phenol adaptation pathways that are transcribed by σ54-dependent RNA polymerases. Our results show that for efficient ATP hydrolysis, MopR assembles as functional hexamers and that this activity of MopR is regulated by its effector (phenol), ATP, and protein concentration. Our findings, and the kinetic methods we employ, should be useful in dissecting the allosteric mechanisms of other AAA+ proteins, in general, and NtrC family members in particular.

Herpes simplex virus retinitis following ChAdOx1 nCoV- 19 (Covishield) vaccination for SARS CoV 2: A case report.

PURPOSE: To report a case of herpes simplex virus retinitis following ChadOx1 nCoV-19 (covishield) vaccination. CASE REPORT: A 29 year old immunocompetent male presented with unilateral disc edema with adjacent retinitis two days after receiving the first dose of ChAdOx1 nCoV-19 vaccination. Extensive investigations to rule out infective etiology were negative except for polymerase chain reaction (PCR) of the vitreous specimen which was positive for the herpes simplex virus. A diagnosis of herpes simplex (HSV) retinitis post covid vaccination was made. The patient responded well to oral antivirals and steroids. CONCLUSION: HSV retinitis is a rare complication following the COVID-19 vaccination.

Structure guided mutagenesis reveals the substrate determinants of guanine deaminase.

Guanine deaminases (GDs) are essential enzymes that regulate the overall nucleobase pool. Since the deamination of guanine to xanthine results in the production of a mutagenic base, these enzymes have evolved to be very specific in nature. Surprisingly, they accept structurally distinct triazine ammeline, an intermediate in the melamine pathway, as one of the moonlighting substrates. Here, by employing NE0047 (a GD from Nitrosomonas europaea), we delineate the nuance in the catalytic mechanism that allows these two distinct substrates to be catalyzed. A combination of enzyme kinetics, X-ray crystallographic, and calorimetric studies reveal that GDs operate via a dual proton shuttle mechanism with two glutamates, E79 and E143, crucial for deamination. Additionally, N66 appears to be central for substrate anchoring and participates in catalysis. The study highlights the importance of closure of the catalytic loop and of maintenance of the hydrophobic core by capping residues like F141 and F48 for the creation of an apt environment for activation of the zinc-assisted catalysis. This study also analyzes evolutionarily distinct GDs and asserts that GDs incorporate subtle variations in the active site architectures while keeping the most critical active site determinants conserved.

Effect of hand-holding and conversation alone or with midazolam premedication on preoperative anxiety in adult patients-A randomised controlled trial.

BACKGROUND AND AIMS: Anxiety causing stress is most profound before surgery. Anxiolytics are used routinely to combat perioperative anxiety. Studies have shown that hand-holding and communication are useful in reducing anxiety levels intraoperatively. This study compares the effectiveness of the same with pharmacological interventions in allaying preoperative anxiety. MATERIAL AND METHODS: This is a three-arm parallel-group randomised controlled trial. A total of 90 adult patients aged <45 years and of American Society of Anesthesiologists (ASA) grade 1-2, undergoing laparoscopic surgery were enroled in this study. Patients received either intravenous (IV) midazolam (group M) or hand-holding and conversation (group HC), or a combination of IV midazolam and holding and conversation (group HCM) in the preoperative room. Anxiety, heart rate (HR) and mean blood pressure (MBP) were recorded before and 20 minutes after the intervention. Anxiety was measured using the Amsterdam preoperative anxiety and information scale. The analysis of covariance (ANCOVA) test was done to analyse the difference between the groups. RESULTS: The mean anxiety scores were significantly different in the three groups (p = 0.04) after intervention, with the lowest score in group HCM, followed by group HC and the highest score in group M. The mean heart rates were also significantly different in the three groups after intervention but MBP was not significantly different in the three groups. CONCLUSION: A combination of hand-holding and conversation and midazolam is best for allaying preoperative anxiety in patients undergoing laparoscopic surgeries than either method alone.