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BackgroundGlomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving alpha3(IV), alpha4(IV), or alpha5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood.Methods and findingsWe showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)--MMP-2, MMP-3, and MMP-9--which influence the progression of renal dysfunction in alpha3(IV)-/- mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the alpha3(IV)-/- mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of alpha3(IV)-/- mice.ConclusionsThese results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in alpha3(IV)-/- mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria.

Glaucoma is a serious sight-threatening disorder aptly named the Silent thief of sight. India, being the second most populous country in the world, has about 20% of the world glaucoma population. The complex geographical and socioeconomic architecture and the economic extremes have a profound effect on its health system. The present times are abundant with fresh developments in the field of glaucoma. Though newer modalities are present in India, they are not ample and are unequally distributed. Adherence and persistence with medical therapy is an issue owing to a multitude of factors. In such a setting, most of the ophthalmologists find themselves performing glaucoma surgeries quite often. In the present era, there are a number of new surgeries to choose from, especially procedures which are nonpenetrating and blebless. Faced with a spectrum of surgeries from shunts to canal surgeries and trabecular bypass devices, the surgeon is often in a dilemma. Still, trabeculectomy remains the gold standard with an increasing trend toward glaucoma drainage devices. The new procedures and devices are worth exploring but await long-term results, good training of surgeons and cost effectiveness.

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug CL on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73 m2 was obtained using the bedside Schwartz equation for some of the subjects, most of whom are children < 2 years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of glomerular filtration rate estimation may be necessary. [ABSTRACT FROM AUTHOR]

Exposure-response (E-R) modeling provides a quantitative tool to leverage adult data to support pediatric trial design and drug approval. The pediatric E-R studies submitted to US Food and Drug Administration (FDA) between 2007 and 2018 were surveyed in the context of various types of trial designs supporting drug approval in the pediatric population. The applications of E-R evaluation in pediatric drug development programs are mainly focused on three areas: (i) supporting pediatric extrapolation when the E-R relationships are similar between the pediatric and adult populations; (ii) dose selection to balance the risk-benefit profile based on the change in efficacy and safety response with different exposure levels; and (iii) approval of a new formulation, new dosing regimen, or new route of administration, where E-R evaluation helps quantify the change in clinical response between the old and new strategies. E-R modeling will continue to play an expanded role in pediatric drug development in the future. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the microbial etiology and associated risk factors among patients with blebitis following trabeculectomy. Materials and Methods: A retrospective analysis of all culture-proven blebitis was performed in patients who underwent trabeculectomy between January 2004 and December 2008. A standardized form was fi lled out for each patient, documenting sociodemographic features and information pertaining to risk factors. Swabbing of the infected bleb surface was performed for all suspected cases and further subjected to microbiological analysis. Results: A total of 23 patients with culture-proven blebitis were treated during the study period, with a mean age of 59.2 years (59.2 + SD: 12.8; range, 30-81 years). Duration of onset was early (< 36 months) in six (26%) cases and late ( > 36 months) in 17 (74%) cases with a range between 15 and 144 months (mean, 82.91 months; SD: 41.89). All 23 blebs were located superiorly and of which, 21 (91%) were microcystic avascular, 1 (4%) diff use avascular, and 1 (4%) vascular fl att ened. The predominant risk factor identifi ed was bleb leak (35%; 8 of 23) followed by thin bleb (22%; 5 of 23) and blepharitis (17%; 4 of 23). Bleb leaks (100%) were recorded only in patients with late onset (> 9 years) of infection (P< 0.001), while the incidence of ocular surface disease (100%) occurred early (< 3 years) (P< 0.001). Use of topical steroids was associated frequently with cases of thin blebs (80%; 4 of 5) (P< 0.001), while topical antibiotics showed bleb leaks (88%; 7 of 8) (P< 0.001). Coagulase-positive staphylococci were frequently recovered from blebitis with thin blebs (71%; 5 of 7) (P = 0.001), Coagulase-negative staphylococci (CoNS) with bleb leak (100%; 8 of 8) (P< 0.001), Corynebacterium with blepharitis (100%; 3 of 3) (P = 0.001), and Streptococci with releasable sutures (75%; 3 of 4) (P = 0.001). Conclusion: Bleb leak is the principal risk factor responsible for late-onset blebitis, while early-onset blebitis could be ascribed to ocular surface diseases. Streptococci were mainly responsible for early onset of infection, while the late onset was due to CoNS. [ABSTRACT FROM AUTHOR]

Objective To elucidate the clinical profile of visual impairment (VI) and the effect of low-vision devices (LVD) among patients with primary open-angle glaucoma (POAG). Methodology A retrospective observational study was used. Case records of patients who reported to the low-vision care clinic with POAG were recruited for the study. Glaucoma was defined according to the International Society for Geographical and EO classification. Demographic data, visual acuity (LogMAR), clinical diagnosis, visual fields, occupation, and LVD prescribed were extracted from the records. The visual acuity pre- and post-use of LVD was compared. Visual acuity improvement while using the LVD was noted. Results Of the 200 POAG cases, 20% (n=40) had severe, 15.5% (n=31) had profound (<3/60), 20.5% (n=41) profound (<1/60), and 26.5% (n=53) had total blindness in the VI category. Significant improvement was noted for both distance and near vision (p=0.004 and p=0.000, respectively) for single-vision glasses, and significant improvement (p=0.000) was also noted for patients corrected for both distance and near correction (bifocal/progressive). Patients with severe visual field loss (p=0.004) and with a visual field defect of <10 degrees (p=0.000) both showed a significant improvement in near vision with low-vision rehabilitation. The proportion of patients earning showed improvement following LVD use compared to those who did not have self-earning (60% vs. 40.24%, p=0.0116). Conclusion LVD significantly improved near vision in POAG patients with advanced glaucoma, a visual field defect of less than 10 degrees. To effectively manage POAG patients with low vision, it is vital to understand both the ocular diseases causing VI and the patient's visual requirements and provide timely management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Paramasivan et al.)

Competing Interests: Competing interests: None declared.