Real world use of loteprednol etabonate ophthalmic gel 0.5% in cases representative of comorbid pathologies responding to minimally invasive glaucoma surgery.

PURPOSE: With the increasing use of minimally invasive surgical techniques for intraocular pressure (IOP) lowering in glaucoma patients, there is a need to examine best practices regarding the postoperative management of these patients. Corticosteroids, though effective in controlling postoperative ocular pain and inflammation, present distinct challenges in glaucoma surgery patients, as their use can be associated with IOP elevation. Loteprednol etabonate (LE) is an ocular corticosteroid designed to have an improved safety profile relative to other corticosteroids. METHODS: We report here a representative selection of cases in which patients were successfully treated with LE ophthalmic gel 0.5% (LE gel) following a variety of minimally invasive glaucoma surgery (MIGS) procedures. Cases included patients undergoing various procedures including a Trabectome combined with cataract surgery; micro-stent surgery (iStent) combined with cataract surgery; supraciliary CyPass Micro-Stent placement combined with cataract surgery; Kahook Dual Blade goniotomy; and ab interno canaloplasty using the iTrack catheter. OBSERVATIONS: In all cases, use of LE gel during the postoperative period appeared effective and safe in reducing inflammation and controlling pain. No adverse events or IOP elevations were noted, even in those patients continuing use of LE gel past the postoperative period for longer than six months with documented follow-up. In two cases, patients with elevated IOP using either prednisolone or difluprednate postoperatively were switched to LE gel, with a subsequent reduction in IOP. CONCLUSIONS: This selection of cases involving patients undergoing MIGS suggests that LE gel may be an effective and safe option for treating postoperative inflammation and pain following such procedures with minimal to no effect on IOP or other negative sequalae.

Do injections of 5-fluorouracil after trabeculectomy have toxic effects on the anterior segment?

OBJECTIVE: To discourage fibrosis of the filtering bleb, 5 fluorouracil (5-FU) may be injected after trabeculectomy. 5-FU is an antimetabolite that also can damage extraocular tissues at concentrations as low as 0.5%. This study ascertained whether repeated injection of 5-FU has toxic effects on intraocular structures. METHODS: After unilateral trabeculectomy in anesthetized New Zealand rabbits, 5-FU (5.0 mg/0.1 mL) was injected at the trabeculectomy site every 5 days for 15 days. Evaluation included slit-lamp examination, confocal microscopy, and intraocular pressure (IOP). After sacrifice, aqueous humor (AH) was drawn and eyes excised for scanning electron microscopy (SEM) and light microscopy. RESULTS: The 5-FU injection not decrease IOP beyond trabeculectomy alone. Bleb height remained constant, thickness increased, and vascularity decreased. No changes in cornea or anterior segment were observed. No inflammation was observed in the bleb or surrounding tissues by slit-lamp or histologic examination. Protein in AH increased from 0.6 +/- 0.5 microg/mL at baseline to 19.8 +/- 4.4 microg/mL after trabeculectomy but only to 0.9 +/- 0.6 microg/mL after trabeculectomy plus 5-FU. Both in vivo confocal microscopy and SEM revealed deleterious effects on corneal epithelial and endothelial cells with a minor shift toward smaller cells. CONCLUSIONS: In this study 5-FU did not provoke an intraocular inflammatory response and had minimal effect on extraocular structures. Changes in corneal epithelium and endothelium detectable by confocal microscopy suggest a small toxic effect. These in vivo measurements by confocal microscopy were confirmed by SEM. Repeated administration did not cause additional cumulative toxic effects in the anterior segment. Therefore, multiple injections of 5- FU into the filtering bleb pose minimal risk to intraocular structures.

Comparison of topical steroids for acute anterior uveitis.

This study objectively compares efficacy of dexamethasone Na phosphate 0.1%, fluorometholone 0.1% (FML), loteprednol etabonate 0.5% (Lotemax [LE]; Bausch & Lomb Pharmaceuticals, Inc., Tampa, FL), prednisolone acetate 1% (Pred Forte [PRED F]; Allergan Pharmaceuticals, Irvine, CA), and generic prednisolone acetate 1% (PRED A). These steroids were administered for 24 hours or 72 hours to New Zealand white rabbits with endotoxin-induced uveitis. Intraocular pressure (IOP), slit-lamp examination, and confocal microscopy were performed daily. Internalization of the glucocorticoid receptor (GC) was assayed in iris tissue by Western blot, and protein in aqueous humor by Bradford assay. Only LE and PRED F treatments significantly internalized GC receptor after 72 hours of treatment. Only LE and PRED A reduced protein concentration between 24 hours and 72 hours of treatment. All drugs improved clinical signs after 24 hours of treatment. None of the steroids promoted return of the inflammation-induced corneal thickness to baseline. While none returned IOP to baseline, LE was most effective. Confocal microscopy indicated that only treatment with LE reverted the abnormal endothelial-cell shape to normal. In conclusion, all steroid treatments reduced uveitis to some degree but LE was consistently effective. A longer observation period may be required to document the return of IOP and corneal thickness to baseline values.

Molecular and conventional epidemiology of Mycobacterium tuberculosis in Botswana: a population-based prospective study of 301 pulmonary tuberculosis patients.

Little is known about patterns of tuberculosis (TB) transmission among populations in developing countries with high rates of TB and human immunodeficiency virus (HIV) infection. To examine patterns of TB transmission in such a setting, we performed a population-based DNA fingerprinting study among TB patients in Botswana. Between January 1997 and July 1998, TB patients from four communities in Botswana were interviewed and offered HIV testing. Their Mycobacterium tuberculosis isolates underwent DNA fingerprinting using IS6110 restriction fragment length polymorphism, and those with matching fingerprints were reinterviewed. DNA fingerprints with >5 bands were considered clustered if they were either identical or differed by at most one band, while DNA fingerprints with < or =5 bands were considered clustered only if they were identical. TB isolates of 125 (42%) of the 301 patients with completed interviews and DNA fingerprints fell into 20 different clusters of 2 to 16 patients. HIV status was not associated with clustering. Prior imprisonment was the only statistically significant risk factor for clustering (risk ratio, 1.5; 95% confidence interval, 1.1 to 2.0). In three communities where the majority of eligible patients were enrolled, 26 (11%) of 243 patients overall and 26 (25%) of 104 clustered patients shared both a DNA fingerprint and strong antecedent epidemiologic link. Most of the increasing TB burden in Botswana may be attributable to reactivation of latent infection, but steps should be taken to control ongoing transmission in congregate settings. DNA fingerprinting helps determine loci of TB transmission in the community.

The birth of ocular pharmacology in the 20th century.

Nineteenth century ophthalmology, characterized by significant gains in diagnostic techniques, provided the basis for great advancements in treatment during the 20th century. Drug therapy at the turn of the century was empiric, palliative, and often toxic. The development of ocular pharmacology during the 20th century provided the basis for a rational therapeutic approach to ocular disease. Foremost among the therapeutic developments were antibiotics, due to their potential to cure conditions that frequently resulted in blindness. Second, other therapeutic classes provided palliative therapy for chronic diseases, and thus decreased morbidity. For example, drugs specifically targeting many different aspects of glaucoma have had remarkable success controlling intraocular pressure and forestalling development of blindness. In addition, other new approaches provided palliative therapy for nonblinding conditions and effective adjuncts to surgical procedures. Antiallergy and anti-inflammatory drugs greatly increased patient comfort and facilitated treatment of allergic and inflammatory reactions. Local anesthetics and analgesia reduced patient discomfort during surgery. Other adjunct drugs improved surgical outcomes by reducing inflammation and infectious complications. The 21st century will undoubtedly provide novel approaches to address many of today's therapeutic dilemmas. Photodynamic therapy, growth factors, antisense technology, and genetic-based therapies all show great promise. Many of the conditions that are only treated palliatively today will be curable in the next century using many of these pharmacological advances.

Using DNA fingerprinting to detect transmission of Mycobacterium tuberculosis among AIDS patients in two health-care facilities in Puerto Rico.

BACKGROUND: Fourteen cases of tuberculosis (TB) in Puerto Rico, diagnosed from April 1993 to April 1995, had the same DNA fingerprint, documenting disease caused by the same strain of Mycobacterium tuberculosis. The 14 cases were retrospectively investigated for epidemiologic links. METHODS: Records were reviewed and staffs of the TB program, hospital/clinic, and AIDS residential facilities were interviewed. RESULTS: Half of the AIDS cases were epidemiologically related, providing evidence of TB transmission in an emergency department, an AIDS inpatient ward, and an AIDS residential facility. DNA fingerprinting allowed detection of M tuberculosis transmission, but contact investigators could have documented it sooner. Factors contributing to transmission included delayed diagnosis, prolonged infectiousness, inadequate discharge planning and infection control procedures, and poor communication between health-care facilities. CONCLUSIONS: The numbers of AIDS residential facilities are increasing and must understand proper monitoring of TB patients and infection control measures that prevent transmissions.

Clinical and programmatic mismanagement rather than community outbreak as the cause of chronic, drug-resistant tuberculosis in Buenaventura, Colombia, 1998.

SETTING: Buenaventura, Colombia. OBJECTIVE: To assess whether antituberculosis drug resistance was generated by poor management or community transmission. DESIGN: Treatment-failure and new tuberculosis (TB) patients identified between May 1997 and June 1998 were interviewed and their treatment histories reviewed. Bacteriologic testing, including drug susceptibility profiles (DSP) and DNA fingerprinting by restriction fragment length polymorphism (RFLP), was performed and human immunodeficiency virus (HIV) testing was offered. RESULTS: DSP and RFLP fingerprints were obtained for isolates from 34 of 64 treatment-failure patients; 25 (74%) were resistant to > or = one drug. Fifteen of the 25 patients consented to HIV testing; none were positive. An average of 2.8 major treatment errors per patient was identified. RFLP from the treatment-failure patients revealed 20 unique isolates and six clusters (isolates with identical RFLP); 4/6 clusters contained isolates with different DSP. Analysis of the RFLP from both treatment-failure and new patients revealed that 44/111 (40%) isolates formed 18 clusters. Four of 47 (9%) new patients had multidrug-resistant TB (MDR-TB). Eleven isolates belonged to the Beijing family, related to the MDR strain W. CONCLUSION: Drug resistance in Buenaventura results from both poor management and community transmission. Dependence on DSP to identify TB transmission is inadequate when programmatic mismanagement is common.

DNA fingerprinting of a national sample of Mycobacterium tuberculosis isolates, Botswana, 1995-1996.

DNA fingerprinting may be useful to elucidate tuberculosis (TB) transmission in community settings, but its utility is limited if only few fingerprint patterns are observed or band numbers are low. We performed DNA fingerprinting on a national, population-based sample of Mycobacterium tuberculosis isolates from Botswana. During 1995-1996, a random sample of 213 isolates, representing 5% of all smear-positive TB cases, underwent DNA fingerprinting using restriction fragment length polymorphism (RFLP) IS6110 analysis. Eighty-two (38%) of the 213 isolates belonged to one of 18 clusters, with 2-9 isolates/cluster. The median number of bands was 10 (range 1-19); 183 (86%) had six or more bands. Sixty-three (49%) of 128 patients tested were infected with the human immunodeficiency virus (HIV). The degree of RFLP pattern heterogeneity and high band number support the feasibility of a prospective DNA fingerprinting study in Botswana.

Application of self-cycling fermentation technique to the production of poly-beta-hydroxybutyrate.

The production of poly-beta-hydroxybutyrate (PHB) by Alcaligenes eutrophus DSM 545 in a cyclone bioreactor was compared using various culture methods: batch, fed-batch, and self-cycling fermentation (SCF) with and without extended periods of nutrient deprivation. SCF is a semi-continuous method that results in a nutrient limitation for every successive generation of cells and, therefore, may have advantages for products whose formation follow secondary metabolite kinetics. Use of the SCF technique without extended nutrient deprivation produced a PHB concentration of 1.2 g L(-1) as 40% of the biomass dry weight. With nitrogen deprivation for 4 or 6 h, the concentration of PHB decreased when compared to the standard SCF technique. However, nitrogen deprivation periods of 8 h resulted in an increase in PHB concentration to 2.7 g L(-1) or 59% of the biomass dry weight. The nutrient cycling may act to repress PHB accumulation during periods of nitrogen deprivation, unless a time threshold has been reached, after which PHB accumulation occurs as in normal batch culture. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 815-820, 1997.

Pars plana Molteno implantation in complicated inflammatory glaucoma.

We retrospectively studied pars plana Molteno implantation in seven patients who had previously undergone multiple attempts, both medical and surgical, to control intraocular pressure (IOP), to no avail. In an effort to avoid further anterior chamber complications, a Molteno implant was inserted through the superior temporal vitrectomy port, following a complete pars plana vitrectomy. Acuity decreased in two of the seven patients due to preexisting conditions and one patient lost vision. Preoperative IOPs ranged from 29 to 57 mm Hg (mean 41 mm Hg) and postoperative IOPs ranged from 7 to 20 mm Hg (mean 12 mm Hg).

Scale-up of a cyclone bioreactor.

The operation of a cyclone bioreactor differs from conventional stirred tanks since the agitation is accomplished by means of a pumped recirculation loop. Oxygen transfer can occur across the swirling gas-liquid interface in the cyclone or from bubbles entrained in the recirculation loop. A cyclone bioreactor was scaled-up from a 1 dm3 bench top unit to a 75 dm3 Process Development Unit (PDU). A reduction in the aspect ratio was compensated for by extending the length of the recirculation loop and providing additional aeration. Performance of the two reactors for the production of microbial poly-beta-hydroxybutyrate (PHB) was compared under various operating conditions. The culture used for PHB production was Alcaligenes eutrophus DSM 545, grown on a mineral salts medium limited by the supply of nitrogen. The levels of dissolved oxygen obtained in the PDU were strongly dependent on the location at which the air was introduced into the reactor. However, with aeration balanced between two injection points and a similar level of power input, 17 J s-1 dm-3, the PDU was able to provide at least as much oxygen transfer capability as the laboratory-scale reactor. Under all conditions tested, the PHB accumulation by A. eutrophus was in excess of 80% of the biomass dry weight, although the yield on glucose was lower in the PDU than in the laboratory-scale reactor.

Ionic channels induced by surfactin in planar lipid bilayer membranes.

Surfactin is a lipopeptide produced by certain strains of Bacillus subtilis and has potent surface activity. Here, we present the first results showing that ion-conducting pores can be formed by surfactin in artificial lipid membranes. With a low aqueous concentration of surfactin (1 microM) and a restricted membrane area (5.10(-5) cm2) we observed conductance jumps that indicate the formation of individual ionic channels in the presence of K+, Rb+, Cs+, Na+ or Li+ chlorides. Although for every salt concentration (Ci), the distribution in amplitude of the conductance steps (lambda i) may be rather broad, there is always a step amplitude which is more frequent than the others. In addition, the channels corresponding to this most frequent step amplitude are the longest in duration. For Ci = 1 M, the cationic selectivity sequence deduced from these most frequent events is K+ greater than Rb+ greater than Na+ greater than Cs+ = Li+ with respective values for lambda Mi: 130, 110, 80 and 30 pS. In KCl solutions lambda MKCl increases as a function of Ci for low Ci, and shows a plateau for Ci greater than 0.5 M. When measured on larger area membranes (10(-2)cm2) with 1 M solutions of the monovalent salts KCl, NaCl, RbCl and CsCl or the divalent salt CaCl2, the macroscopic low voltage conductance (G0) increases with a slope of 2 on a log-log plot as a function of surfactin concentration. These results demonstrate that surfactin produces selective cationic channels in lipid bilayer membranes and suggest that at higher salt concentration, a dimer is involved in this functional channel-forming process.

The effects of a biosurfactant on oxygen transfer in a cyclone column reactor.

A laboratory-scale cyclone column reactor was tested to determine how its oxygen transfer characteristics were affected by surfactants in the liquid medium. The volumetric oxygen transfer coefficient was greatly decreased by small quantities of the synthetic surfactants dodecyltrimethylammonium bromide and sodium dodecylsulfate, and the biosurfactant surfactin produced by Bacillus subtilis (ATCC 21332). Since the gas holdup fraction was generally increased due to foaming, the effectiveness of the surfactants was probably due to an increase in the interfacial film resistance. B. subtilis was grown in the cyclone column to 0.6 g dm-3 with a significant level of surfactin produced while maintaining at least 75% oxygen saturation in the broth. Process optimization and scale-up of surfactin production will have to consider oxygen transfer as a key parameter.

The ocular surface in cystic fibrosis.

Seventeen patients with cystic fibrosis and 17 age-, race-, and sex-matched controls were examined under standardized conditions. Testing included slit-lamp biomicroscopy, fluorescein staining, rose bengal staining, Schirmer's basic tear test, tear film break-up time, tear pH, tear lysozyme, tear protein, lid and conjunctival cultures, and conjunctival impression cytology. Cystic fibrosis patients showed a statistically significant increase in the incidence of fluorescein staining and clinical blepharitis, as well as significantly decreased Schirmer testing and tear lysozyme. Ocular surface abnormalities in these patients may be attributable to aqueous and lipid tear film deficiencies. Cystic fibrosis patients showed normal conjunctival epithelial cell morphology, grew no pathogenic organisms, and had a decreased incidence of conjunctival bacterial colonization.

Immunodiagnosis of adult chlamydial conjunctivitis.

This study presents data from a prospective comparison of four currently available diagnostic tests for Chlamydia trachomatis infection. Seventy-six patients clinically suspicious for chlamydial conjunctivitis were all tested with Giemsa stain cytology, direct monoclonal fluorescent antibody (DFA) microscopy, enzyme immunosorbent assay (EIA) for chlamydial antigens, and standard McCoy cell culture. When compared with primary cell culture, diagnostic Giemsa inclusions had a sensitivity and specificity of 43 and 100%, respectively, supportive Giemsa cytology 71 and 67%, the enzyme immunoassay 71 and 97%, and the monoclonal fluorescent antibody 57 and 81%. Each nonculture method has distinct advantages in terms of cost, technical difficulty, speed, and accuracy, which dictate selection of the most appropriate test for office or laboratory diagnosis of chlamydial conjunctivitis.

Oral haloperidol lowers human intraocular pressure.

This is a double masked, randomized, crossover design trial of orally administered haloperidol in human volunteers. There was a statistically significant drop of the intraocular pressure in non-glaucomatous volunteers at 3 and 4 hours following haloperidol administration. Glaucomatous patients on topical medications did not show a statistically significant drug effect. Non-glaucomatous volunteers showed a statistically significant decrease in pupillary diameter 3 hours following haloperidol administration while glaucomatous subjects showed no significant change in pupillary diameter. There were no significant changes in the near point of accomodation. Dopamine antagonists like haloperidol may act by blocking post-synaptic dopamine receptors in the ciliary body, resulting in vasoconstriction and subsequently decreased aqueous humor production. Pharmacologic data from human use suggests that ocular side effects of topically administered haloperidol may be less than those of pilocarpine, while systemic side effects may be less than those of timolol. Haloperidol may become a cost-effective, once daily ocular hypotensive agent. Problems with preparation of a viable topical vehicle, as well as potential long-term side effects will require a great deal of further investigation.