Factors related to survival and treatment success in invasive candidiasis or candidemia: a pooled analysis of two large, prospective, micafungin trials.

Crude and attributable mortality rates in patients with candidemia and invasive candidiasis remain unacceptably high. It is important to reach a more complete understanding of the risk factors underlying poor outcomes in patients with invasive Candida infections. Micafungin therapy has been assessed in two phase 3 trials compared to either liposomal amphotericin B or caspofungin. The availability of this large dataset allows the analyses of non-drug factors associated with survival and treatment success. A multivariate regression analysis was performed on data from the two trials separately and as a pooled analysis (N = 1,070). Analysis outcomes were survival at 42 days post-initiation of therapy and treatment success. For the pooled analysis, treatment success was significantly more likely for candidemia than invasive candidiasis. Both survival and treatment success were significantly less likely for the non-removal of catheter versus removal, Asian-Indians versus Caucasians, APACHE II score >20 to 30 versus or=70 years versus <50 years, baseline corticosteroids, and persistent neutropenia. Survival was also significantly less likely for treatment in other regions versus North America and for patients with renal failure at baseline. These findings help to define non-antifungal drug factors that may impact survival and treatment success in invasive candidiasis or candidemia.

Effect of thiol-oxidation of glutathione with diamide on corneal endothelial function, junctional complexes, and microfilaments.

Intracellular-reduced glutathione (GSH) was removed by thiol-oxidation with diamide during in vitro perfusion of the corneal endothelium. By 15 min the normal mosaic-like pattern of the endothelial cells was disrupted by serpentine-like lines of cell separation at the cell juntions. After 45 min of perfusion, infividual clusters of cells formed cup-shaped islands. The resultant exposure of Descemet's membrane to the perfusion solution resulted in corneal swelling. Transmission electron microscopy revealed that the endothelial cells separated at the apical junctions and that the microfilaments in the apical cytoplasm of cells formed dense bands, whereas the other subcellular organelles were normal in appearance. The change in cellular shape may be due to loss of cellular adhesion which results in the condensation of the microfilaments or contraction of the microfilaments. The addition of glucose to the perfusate prevented the diamide effect, and the diamide effect could be reversed upon removal and perfusion of a glutathione bicarbonate Ringer's solution. These results suggest that the ratio of reduced to oxidized glutathione in the endothelial cells plays a role in the maintenance of the endothelial cell barrier function.

Central nervous system involvement in cryptococcal infection in individuals after solid organ transplantation or with AIDS.

BACKGROUND: Cryptococcus neoformans is an important pathogen of immunocompromised hosts. Manifestations of cryptococcal infection have not been compared between populations based on the nature of the underlying immune deficiencies. METHODS: The Prospective Antifungal Therapy Alliance (PATH) is a registry that collects clinical data from patients with invasive fungal infections from medical centers in North America. Univariate analyses and group comparisons were conducted from the PATH registry for cases of infection due to Cryptococcus species occurring between March 2004 and April 2008. RESULTS: A total 235 cases of proven infection due to Cryptococcus species were documented, all of which were due to C. neoformans (52 in solid organ transplant [SOT] recipients, 107 in patients infected with the human immunodeficiency virus [HIV], and 76 with neither HIV nor organ transplantation). A total of 140 cases manifested as meningitis (25 in SOT recipients, 88 in HIV-positive patients, and 27 in those with neither risk factor). Of individuals with cryptococcal infection, 44.2% of SOT recipients had central nervous system (CNS) disease, while 84.1% of those with HIV infection presented with CNS involvement (P=0.0265). SOT recipients receiving calcineurin inhibitors (CNIs) were less likely to have CNS involvement in cryptococcal infection (40.1% versus 66.7%). Overall, 12-week mortality for patients with cryptococcal infection in the PATH Alliance registry was 22.6% (21.2% for SOT, 15.9% for HIV-infected patients, and 32.9% for patients with risk factors other than HIV infection or organ transplantation). CONCLUSIONS: In a prospectively assembled cohort of individuals with proven infection due to C. neoformans, CNS involvement was more common in individuals with HIV infection than in SOT recipients. The role of CNIs in the reduction of risk for CNS cryptococcosis remains to be defined. Overall survival of patients with cryptococcal infection in immunocompromised hosts has improved over time. Observed differences in the context of various host immune deficits provide a basis for further investigation of cryptococcosis and other opportunistic infections.

Behavioral inhibition and clinical outcomes in children with cochlear implants.

OBJECTIVES/HYPOTHESIS: Individual speech and language outcomes of deaf children with cochlear implants (CIs) are quite varied. Individual differences in underlying cognitive functions may explain some of this variance. The current study investigated whether behavioral inhibition skills of deaf children were related to performance on a range of audiologic outcome measures. DESIGN: Retrospective analysis of longitudinal data collected from prelingually and profoundly deaf children who used CIs. METHODS: Behavioral inhibition skills were measured using a visual response delay task that did not require hearing. Speech and language measures were obtained from behavioral tests administered at 1-year intervals of CI use. RESULTS: Female subjects showed higher response delay scores than males. Performance increased with length of CI use. Younger children showed greater improvement in performance as a function of device use than older children. No other subject variable had a significant effect on response delay score. A series of multiple regression analyses revealed several significant relations between delay task performance and open set word recognition, vocabulary, receptive language, and expressive language scores. CONCLUSIONS: The present results suggest that CI experience affects visual information processing skills of prelingually deaf children. Furthermore, the observed pattern of relations suggests that speech and language processing skills are closely related to the development of response delay skills in prelingually deaf children with CIs. These relations may reflect underlying verbal encoding skills, subvocal rehearsal skills, and verbally mediated self-regulatory skills. Clinically, visual response delay tasks may be useful in assessing behavioral and cognitive development in deaf children after implantation.

Pathologic findings in the aortocoronary vein grafts. A scanning electron microscope study.

Examination of totally or partially obstructed human aortocoronary vein grafts, obtained at different time intervals after the bypass operation, has shown that the initial occlusive process is due to thrombosis and may appear a few hours or days after surgery. The cellular phase of intimal proliferation affecting most of the grafts becomes apparent about 4 weeks after the operation. After 1 year the intimal hyperplasia acquires a cell-poor, fibrotic character; the graft usually remains patent. About one-half of the vein grafts obtained 3 or more years after the operation show complicated atherosclerotic lesions. These findings indicate that most of the vein grafts undergo extensive structural changes and some may show similar degenerative lesions as they develop in the coronary arteries.

The effects of ketamine sedation and ketamine-pentobarbital anesthesia upon the intraocular pressure of the rabbit.

The effect of ketamine sedation and ketamine-pentobarbital anesthesia upon the intraocular pressure (IOP) of the rabbit was studied by applanation pneumatonography. Peak values of IOP during both ketamine sedation and ketamine-pentobarbital anesthesia were reached 3 to 5 minutes after administration of the drug(s). The peak IOP increase during ketamine sedation (10 mg./kg. IM) was 2.2 +/- 0.4 mm. Hg. The peak IOP increase with ketamine-pentobarbital anesthesia (50 mg./kg. ketamine IM + 30 mg./kg. pentobarbital IM) was 7.1 +/- 0.8 mm. Hg. Atropine premedication did not prevent the increase in IOP seen with ketamine sedation or ketamine-pentobarbital anesthesia.

The effects of increased hydrostatic pressure upon normal and regenerated rabbit corneal endothelium.

The effect of increased hydrostatic pressure upon the ability of normal and regenerated endothelium to deturgesce preswollen, de-epithelialized rabbit corneas was studied. Stromal deturgescence occurred as a biphasic response when hydrostatic pressure at the endothelial surface was increased above baseline values. Initially there was a rapid phase of stromal thinning which was dependent upon hydrostatic pressure nad endothelial function. This was followed by a slower phase of corneal thinning which was independent of hydrostatic pressure at the endothelial surface for pressures between 15 and 50 mm Hg. The slow phase of thinning represents the steady-state ability of the endothelium to deturgesce the stroma. Regenerated rabbit endothelium functioned similarly to normal endothelium in deturgescing the stroma. In addition, short-term increases in hydrostatic pressure at the endothelial surface did not produce ultrastructural changes in normal or regenerated corneal endothelial cells.

The effects of aging and inflammation on corneal endothelial wound healing in rabbits.

After transcorneal freezing, the rates and patterns of corneal endothelial wound healing were compared in mature and young rabbits by autoradiographic analysis of 3H-thymidine incorporation and scanning electron microscopy. Healing was slower and less extensive in mature corneas than in young ones. Regardless of animal age, however, healing occurred by cell division and the migration of newly divided cells onto the wound surface. Spontaneously occurring severe inflammation appeared to reduce the ability of corneal endothelial cells to replicate their DNA.

The pH tolerance of rabbit and human corneal endothelium.

The endotheliums of rabbit corneas were perfused in an in vitro perfusion specular microscope up to 3 hr with solutions varying in pH from 3.5 to 10.0. Corneal thickness was monitored throughout the experiment, and at appropriate times the corneas were prepared for SEM and TEM. Analysis of the corneal thickness data and interpretation of the electron micrographs reveals that outside of the pH range of 6.5 to 8.5, structural and functional alterations occur. Direct cellular damage, as well as disruption of junctional complexes, lead to a breakdown in the barrier function of the corneal endothelium. The extent of this breakdown is dependent upon both the magnitude of the pH change and the exposure time. Further experiments on banked human eyes support this finding.

Effects of transcorneal freezing on protein content of aqueous humor and intraocular temperature in rabbit and cat.

The effects of transcorneal freezing on protein content of aqueous humor and intraocular temperature at the posterior surface of the cornea, the angle, the iris, and the ciliary processes were determined in rabbits and cats. Normal aqueous protein concentration was 40 +/- 2 mg/dl in rabbits and 43 +/- 4 mg/dl in cats. In rabbits, total aqueous protein content reached its highest level (2790 +/- 302 mg/dl) for 3 hr after transcorneal freezing, decreased by 50% after 4 hr, and was not significantly different than normal at 7 days. In cats, total aqueous protein content also reached its highest level (1610 +/- 290 mg/dl) 3 hr after corneal freezing. Fluctuations occurred thereafter, but protein content was not significantly different from normal after 7 days. The temperature at the corneal endothelium always decreased to below 0 degrees C with a 10 to 25 sec application of the cryoprobe to the cornea in rabbit and cat. Intraocular temperature did not decrease below 24 degrees C at the angle or ciliary processes during application of the cryoprobe for up to 25 sec, whereas the temperature at the pupillary margin of the iris sometimes decreased to near 0 degrees C with a 15 to 25 sec application.

The role of thyroid hormone in the development of the chick corneal endothelium and epithelium.

Previous studies have established that thyroxine or thiouracil treatments affect the development of corneal transparency in the chick. The effects of these drugs on chick corneal epithelial and endothelial development were investigated because in the adult the integrity of these cell layers is necessary for the maintenance of corneal transparency. Chick embryos were treated with thiouracil or thyroxine at stage 36 or 38; the corneas were excised 2 to 12 days after treatment (between stages 38 and 45), and prepared for electron microscopy. The colloidal tracer ruthenium red was added during fixation to study epithelial and endothelial permeability and to stain the intercellular endothelial spaces. At all stages studied, the epithelium was impermeable to ruthenium red and this property was not affected by drug treatment. The epithelial barrier to this tracer is located in the outermost cell layer. The ease of penetration of ruthenium red through the endothelial intercellular spaces indicated the lack of zonular tight functions and the presence of gap functions in this cell layer. Thiouracil treatment delayed the development of the corneal epithelium so that at stage 45 it resembled epithelium from a normal embryo 3 stages younger. In normal animals, chick corneal endothelial development is characterized by an increasing degree of interdigitation of the lateral plasma membranes of adjacent endothelial cells with advancing embryonic age. Thiouracil treatment delayed this progressive development of adjacent cell membrane interdigitation. In contrast, thyroxine treatment accelerated the development of the lateral borders of the endothelial cells. It also appears that thyroid hormone can affect the development of the cell membranes of apposed cells in epithelium as well as the endothelium of the embryonic chick cornea.

Effect of phenylephrine on normal and regenerated endothelial cells in cat cornea.

Topical commercial phenylephrine HCl (Neo-Synephrine 10%) has been shown to cause an increase in corneal thickness and reversible vacuolization of corneal endothelial cells in rabbits. Using an in vivo model of regenerated corneal endothelial cells in the cat, we compared the cytotoxicity of phenylephrine-HCl 10% to regenerated and to normal, nonregenerated cells. Following removal of the epithelium, topical application of the drug causes the appearance of anterior and posterior bands of stromal edema and reversible vacuolization in both normal and regenerated endothelial cells. Phenylephrine was not more damaging to the regenerated cells. Polymorphonuclear leukocytes infiltrated between the regenerating cells 24 hr after treatment but did not appear to destroy them. Phenylephrine may therefore be implicated as a causative factor of corneal edema and postoperative inflammation.

Pathogenesis of experimental Pseudomonas keratitis in the guinea pig: bacteriologic, clinical, and microscopic observations.

Uniformly severe corneal infections were produced in guinea pigs by intracorneal injection of about 10 viable Pseudomonas aeruginosa. After a brief lag period, multiplication of bacteria was rapid, reaching geometric means of 280,000 after 24 hr and of 5 million after 48 hr. Within 8 hr after inoculation, polymorphonuclear leukocytes (PMNs) began to infiltrate the anterior two thirds of the stroma. Stromal cells adjacent to the injection site became necrotic and appeared to be engulfed by PMNs. By 14 to 16 hr, an abscess containing a dense aggregate of PMNs and multiplying bacteria developed in the central stroma. By 16 to 24 hr, collagen breakdown was apparent within and around the abscess. Ultrastructural evidence of collagen breakdown included loss of intact collagen fibrils, tactoid formation, and accumulation of amorphous electron-dense material. The area of liquefactive necrosis gradually enlarged, and many corneas perforated after 3 to 4 days. Because the course of infection is highly reproducible, this model should prove useful for many studies of experimental Pseudomonas keratitis.

Effect of the ophthalmic preservative thimerosal on rabbit and human corneal endothelium.

Widespread use of the mercurial-containing preservative thimerosal as an antibacterial agent in ophthalmic drugs and solutions warranted an investigation into its possible cytotoxic effects on the functional and ultrastructural integrity of the corneal endothelium. No changes in corneal thickness were observed during 5 hours' perfusion of the endothelium of rabbit and human corneas with 0.0001 and 0.0005 percent thimerosal in glutathione bicarbonate Ringer's solution (GBR). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) of the endothelium of the 0.0001 percent group revealed normal ultrastructure. SEM and TEM of the endothelium of corneas perfused with 0.0005 percent thimerosal for 5 hours revealed condensed mitochondria, cytoplasmic vacuoles, and cytoplasmic flaps at the apical end of the cellular junctions. Perfusion of higher concentrations (0.001 and 0.005 perecnt) of thimerosal in GBR resulted in increases in corneal thickness after 2 hours and irreversible ultrastructural damage to the endothelial cells by 5 hours. Corneas perfused with 0.01 and 0.1 percent thimerosal in GBR showed a rapid and immediate increase in corneal thickness and endothelial cell death and necrosis within 1 hour. It is postulated that the mercury in thimerosal becomes bound to the cell membrane protein sulfhydryl groups, causing an increase in cellular permeability; These results suggest that the prolonged exposure of the corneal endothelium to thimerosal in the accepted antimicrobial dosage of 0.005 to 0.001 percent may result in functional and structural damage to the endothelium.

Experimental Pseudomonas keratitis in the rabbit: bacteriologic, clinical, and microscopic observations.

Uniformly severe corneal infections were produced in rabbits by intracorneal injection of a few viable Pseudomonas aeruginosa. The bacteria multiplied rapidly, and within 24 hr, about 10 million organisms were present. The numbers remained stable thereafter. Polymorphonuclear leukocytes (PMNs) began to infiltrate peripheral stroma 24 hr after inoculation. By 32 hr, ring-shaped dense accumulations of PMNs were apparent in the anterior stroma with moderate stromal edema. By 48 hr, the anterior one third of central stroma was severely involved with abscess formation and loss of epithelium, and PMNs had invaded full corneal thickness. The area of liquefactive necrosis eventually involved the entire cornea from limbus to limbus, and collagen staining was lost. Transmission electron microscopy revealed the accumulation of small electron-dense particles in association with collagen fibrils and degranulating PMNs.

Corneal endothelial autoradiography with the scanning electron microscope.

A new technique for performing corneal endothelial cell autoradiography with the scanning electron microscope is presented. The scanning electron microscope is able to detect silver grains deposited over tritiated thymidine--labeled nuclei of regenerating corneal endothelium.

Xerophthalmia in vitamin A-deficient rabbits. Clinical and ultrastructural alterations in the cornea.

Xerophthalmia developed in the eyes of rabbits maintained on a vitamin A-deficient diet for 4 to 6 months. The earliest clinical change, a lusterless graying of the central corneal epithelium, was noted after 16 to 18 weeks on the diet. Multiple small punctate epithelial erosions appeared in the interpalpebral fissure zone within 7 to 10 days after the lusterless graying became evident. The erosions gradually became confluent, and a striking dry, glazed, peau d'orange appearance was noted. Polycystic microbullae appeared in the epithelium in some eyes. Thick keratinized epithelial plaques developed in all eyes 1 to 2 weeks after the appearance of severe peau d'orange. Electron microscopy of corneas with lusterless graying of the epithelium revealed swelling of the most superficial epithelial cells with flattened and shorter microvillous projections. In corneas with punctate epithelial erosions and keratinized plaques, microvilli were absent or decreased in number on superficial cells, and multilayered, keratinized epithelial cells were present on the surface of the cornea. The stroma appeared essentially normal with minimal edema at all stages when examined by electron microscopy. Intercellular edema was present in the endothelium in early- and late-stage xerotic corneas but could not be detected clinically. No significant clinical or microscopic alterations were seen in the corneas of control rabbits on normal diet or in rabbits on the vitamin A-deficient diet supplemented with vitamin A. The alterations seen in the corneas of vitamin A-deficient rabbits are similar to those which have been described in vitamin A-deficient humans. Rabbit therefore appears to be a good model for further studies of xerophthalmia.

Late lesions in aorta-coronary artery vein grafts.

Aorta-coronary artery vein grafts, obtained from 2 patients 37 and 59 months after an aorta-coronary bypass operation, showed extensive mural changes characterized by degenerative tissue lesions, loss of normal morphological features of the intima, and extracellular accumulation of lipids. Both patients had increased plasma triglyceride levels.

Susceptibility of group A beta-hemolytic streptococci to thirteen antibiotics: examination of 301 strains isolated in the United States between 1994 and 1997.

BACKGROUND: Because of continuing reports from many countries of increasing resistance of group A streptococci to macrolide antibiotics, we determined the antibiotic susceptibility of recent group A streptococcal isolates from the United States. METHODS: We evaluated 301 Streptococcus pyogenes isolates (245 from patients with uncomplicated pharyngitis and 56 isolates from patients with invasive systemic infections) for susceptibility using the Etest technique. The isolates came from 24 states and the District of Columbia during the years 1994 through 1997. Thirteen antibiotics (azithromycin, ceftriaxone, cephalothin, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, imipenem, levofloxacin, oxacillin, penicillin G, tetracycline and trimethoprim-sulfamethoxazole) were studied. RESULTS: The MIC90 for penicillin was 0.016 microg/ml, which is not significantly different from previous reports. Of the 301 isolates only 2.6% were resistant to a macrolide antibiotic and only 4% were resistant to tetracycline. CONCLUSIONS: These data indicate that antibiotic resistance among recent isolates of group A streptococci (including those from patients with severe infections) currently is not a clinically significant problem in the United States.

Intraocular irrigating solutions. A comparative study of BSS Plus and lactated Ringer's solution.

Isolated human corneas maintained normal corneal thickness and endothelial ultrastructural integrity throughout a three-to four-hour period of perfusion of BSS plus to the endothelial surface. By comparison, only one of six human corneas perfused with lactated Ringer's solution was able to maintain normal thickness and ultrastructural integrity. The other five corneas perfused with lactated Ringer's solution showed various degrees of endothelial cell breakdown and corneal swelling during three hours of perfusion. The results of these studies suggest that BSS plus is a better solution for maintenance of human corneal endothelium during long-term (one- to three-hour) surgical procedures.