Transcriptional down-regulation of ccr5 in a subset of HIV+ controllers and their family members.

HIV +Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4 +T cells with resistance specific to R5-tropic HIV, reversed after introduction of ccr5. R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4 +T cells of these EC/VCs had lower ccr2 and ccr5 RNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of ccr2 and ccr5, despite having more accessible chromatin by ATAC-seq. Other nearby genes were also down-regulated, over a region of ~500 kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with ccr2/ccr5 down-regulation, suggesting that the phenotype is heritable.

Corneal collagen crosslinking in patients treated with dextran versus isotonic hydroxypropyl methylcellulose (HPMC) riboflavin solution: a retrospective analysis.

BACKGROUND: Corneal collagen crosslinking (CXL) is a widely used treatment for halting the progression of keratoconus. Although initial studies of CXL were performed with a riboflavin solution containing dextran, recent protocols for CXL have indicated the use of a riboflavin solution containing isotonic hydroxypropyl methylcellulose (HPMC). This study was performed to investigate differences in visual outcomes and Scheimpflug (Pentacam) analysis in patients who have undergone epithelium-off CXL with riboflavin solution containing either 20% dextran versus 1.1% HPMC. METHODS: All patients in this non-randomized, non-masked, retrospective cohort analysis were treated at Edward S. Harkness Eye Institute, Columbia University Medical Center, New York, NY, USA. Thirty-seven eyes of 33 patients were crosslinked with a dextran solution and 19 eyes of 19 patients crosslinked with an isotonic HPMC solution, both using an epithelium-off 30-min, 3 mW/cm2 protocol. All patients had a diagnosis of keratoconus or post-refractive surgery ectasia. Best spectacle corrected visual acuity (BSCVA) and Pentacam parameters were compared at all follow up visits (1, 6, 12, and 24 months). Differences between groups treated with HPMC and dextran were compared using student's t-test. Differences between treated eye and fellow eye were calculated and compared between HPMC and dextran groups using paired t-test. RESULTS: Patients treated with a dextran solution had significantly greater improvement in BSCVA at 1, 6, and 24 months (p < 0.05) compared to the isotonic HPMC-treated group. Kmax increased in both groups at 1 month; however, HPMC-treated patients had a greater increase compared to dextran-treated patients (p = 0.01). Kmax decreased in both groups at 6 and 12 months, although this finding was only significant in the HPMC-treated group at 12 months. CONCLUSIONS: Our data suggest that crosslinking with the dextran solution may result in significantly better visual outcomes (demonstrated by visual acuity) compared to the isotonic HPMC riboflavin solution. Dextran solutions may have other potential advantages intrinsic to its biochemical properties facilitating more efficient crosslinking. Further research and long-term evidence regarding the use of dextran versus HPMC riboflavin solutions in collagen crosslinking is necessary.

Correlation of Scheimpflug densitometry changes with clinical outcomes after corneal crosslinking.

PURPOSE: To characterize changes in densitometry after corneal crosslinking (CXL) and correlate it with visual outcomes. SETTING: Tertiary referral academic medical center, New York, New York, USA. DESIGN: Retrospective case series. METHODS: Patients with progressive keratoconus or post-laser in situ keratomileusis ectasia had CXL following the Dresden protocol. The corrected distance visual acuity (CDVA) and Pentacam imaging were obtained at baseline and follow-up visits. RESULTS: Fifty-seven patients were followed for a mean of 15 months (range 1 to 24 months) after CXL. The CDVA improved significantly from baseline to 6, 12, 18, and 24 months postoperatively. The change in densitometry of the mid-stromal layer, 2.0 to 6.0 mm annulus, at 6 months was correlated with the improvement in CDVA at 6, 12, and 24 months (all P < .10). The increase in densitometry of the mid-stromal layer, centermost 0.0 to 2.0 mm annulus, at 6 months was significantly associated with the decrease in maximum keratometry (K) at 6 and 12 months (both P < .05). Last, the change in densitometry at 6 months was significantly correlated with the decrease in specific higher-order aberrations (HOAs) (P < .05). CONCLUSIONS: Although the greatest and most durable post-CXL densitometry change was in the anterior layer, the degree of increased densitometry haze in the mid-stromal layer was most associated with and possibly predictive of improvement in CDVA, maximum K, and HOAs. The persistence of corneal haze at 6 months, measured by increased densitometry, might be a prognostic marker for CXL effectiveness.

Antimicrobial Studies Using the Therapeutic Tissue Cross-Linking Agent, Sodium Hydroxymethylglycinate: Implication for Treating Infectious Keratitis.

Purpose: Our recent studies raise the possibility of using sodium hydroxymethylglycinate (SMG), for pharmacologic therapeutic tissue cross-linking (TXL) of the cornea. The present study was performed to evaluate the antimicrobial effects of SMG for potential use in treating infectious keratitis. Methods: In initial (group 1) experiments, methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa (PA) were treated with SMG (10-40 mM) for 10 to 120 minutes. In group 2 experiments, MRSA, PA, Candida albicans (CA), and vancomycin-resistant Enterococcus (VRE) were treated with SMG (20-200 mM) for 30 minutes. In group 2 experiments, BSA and neutralizing buffer were added to provide a proteinaceous medium, and to ensure precise control of SMG exposure times, respectively. SMG effectiveness was quantitated based on pathogen growth following a 24- to 48-hour incubation period. Results: In group 1 experiments, as expected, time- and concentration-dependent bactericidal effects were noted using MSSA. In addition, the effect of SMG (40 mM) was greatest against MSSA (99.3%), MRSA (96.0%), and PA (97.4%) following a 2-hour exposure with lesser effects following 30- and 10-minute exposures. In group 2 experiments, concentration-dependent bactericidal effects were confirmed for MRSA (91%), PA (99%), and VRE (55%) for 200-mM SMG with 30-minute treatment. SMG was not as effective against CA, with a maximum kill rate of 37% at 80 mM SMG. Conclusions: SMG solution exhibits a dose-dependent bactericidal effect on MSSA, MRSA, and PA, with milder effects on VRE and CA. These studies raise the possibility of using SMG TXL for the treatment of infectious keratitis.