[Induced Incomitance of one Muscle Strabismus Surgery in Comparison to Unilateral Recess-Resect Procedures]. / Einseitige Einmuskel- gegen Zweimuskelchirurgie: Vergleich der induzierten Inkomitanz.

BACKGROUND: Surgical correction of intermediate squint angles may be performed on one muscle alone or as a combined unilateral recess-resect procedure. No larger case series has yet systematically measured the amount of induced incomitance that could potentially lead to visual disturbances. METHODS: 31 patients with strabismus and binocular vision (phoria or intermittent strabismus) were operated on one extraocular eye muscle; 30 patients underwent a unilateral recess-resect procedure. Preoperatively and three months postoperatively, we measured the latent angle of squint on a tangent screen over the horizontal 60° in 10° increments and then calculated the amount of induced incomitance. RESULTS: After one muscle surgery, the induced incomitance was 1.7° over a 20° gaze range, 3.2° over a 40° gaze range and 3.8° over a 60° gaze range. For recess-resect procedures, the induced incomitance was 1.4°, 2.6° and 3.4°, respectively. A significant correlation between the surgical dose and the induced incomitance was only seen in one muscle surgery for the 40° and 60° gaze range, but not for the 20° gaze range. A subgroup analysis of patients with an identical surgical dose in one and two muscle procedures (6-8 mm) found greater induced incomitance in one muscle procedures, but only for the 40° and 60° gaze range (p = 0.02). Double vision in any gaze direction was reported by 16 % of patients after one muscle surgery and 10 % of patients after unilateral recess-resect surgery (p > 0.05). CONCLUSION: One muscle surgery is a viable option in small and intermediate angles of squint. The induced incomitance is rather small and does not lead to significant visual disturbances in the central gaze range.

[Perforating keratoplasty versus Descemet stripping automated endothelial keratoplasty in the partner eye: Functional results and patient satisfaction]. / Perforierende Keratoplastik vs. "Descemet stripping automated endothelial keratoplasty" im Partnerauge : Funktionelle Ergebnisse und Patientenzufriedenheit.

BACKGROUND: This study compared the postoperative results and patient satisfaction between penetrating keratoplasty (PK) and Descemet stripping automated endothelial keratoplasty (DSAEK) in patients who underwent PK in one eye and DSAEK in the other eye. METHODS: A total of 15 patients were identified from the corneal database register and the medical charts were analyzed for best corrected visual acuity (BCVA), keratometric astigmatism, endothelial cell density and postoperative complications. Patient satisfaction was evaluated by a standardized interview. RESULTS: Median follow-up time for PK was 55 months and 18 months for DSAEK (p < 0.01). Median BCVA in PK was 0.8 and 0.5 in DSAEK (p = 0.01) at the end of follow-up. Median keratometric astigmatism was 3.1 diopters after PK and 1.9 diopters after DSAEK (p = 0.2). Median endothelial cell density was 831 cells/mm(2) after PK and 860 cells/mm(2) after DSAEK (p = 0.63). For the interventions 57 % of the patients preferred PK, 36 % preferred DSAEK and 7 % were undecided. Patients assigned the better performing eye to the PK side in 64 % and in 29 % to the DSAEK side and 7 % perceived equal visual performance in both eyes. CONCLUSION: The results leave doubt about the superiority of DSAEK compared to PK; however, exceptionally good refractive results of the 15 PK eyes analyzed and significantly longer follow-up times after PK could be the reason for the unexpectedly high patient preference for PK.

[Prevalence of glaucoma in obstructive sleep apnea]. / Glaukomprävalenz bei obstruktiver Schlafapnoe.

BACKGROUND: A causal relationship between glaucoma and obstructive sleep apnea has been postulated in several clinical studies but also refuted by others. The aim of this study was to determine the prevalence of glaucoma in a cohort of patients with well-established obstructive sleep apnea in comparison to the published data on this topic. METHODS: A total of 100 consecutive patients (male:female 80:20, mean age 59 ± 11 years SD) with polysomnographically established obstructive sleep apnea underwent an ophthalmological examination including tonometry, static perimetry and dilated fundus photography. Visual fields and fundus photographs of the patients were classified as glaucomatous or non-glaucomatous by two independent examiners. RESULTS: The prevalence of glaucoma in the study patients was 2 % which corresponded to the published prevalence of glaucoma in the normal population. Intraocular pressure did not correlate with the respiratory index, body mass index or sex. CONCLUSION: The data from this study shed doubt on a causal relationship between obstructive sleep apnea and glaucoma.

Alternative mechanisms for tiotropium.

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Rapamycin reduces VEGF expression in retinal pigment epithelium (RPE) and inhibits RPE-induced sprouting angiogenesis in vitro.

Anti-VEGF treatment has become accepted first-line treatment for choroidal neovascularisation (CNV) in age-related macular degeneration. However, VEGF-inhibition does not always lead to sustained CNV-reduction. In this study, the effect of rapamycin was superior to VEGF-inhibition in a co-culture assay of endothelial cells (ECs) and retinal pigment epithelium (RPE). Rapamycin reduced EC sprouting in groups that did not respond to anti-VEGF treatment. Rapamycin did not induce EC apoptosis, but reduced both VEGF-production in RPE and the responsiveness of ECs to stimulation. Rapamycin might therefore be a therapeutic option for CNV patients that do not respond sufficiently to the established anti-VEGF treatments.

Extrapulmonary effects of chronic obstructive pulmonary disease.

Although airflow obstruction is the most obvious and most studied manifestation of chronic obstructive pulmonary disease (COPD), it should not be overlooked that COPD, particularly in its later stages, is associated with many extrapulmonary features that contribute to the morbidity, reduced quality of life, and, possibly, mortality of this disease. We review here the literature on skeletal muscle dysfunction, osteoporosis, and weight loss in COPD, with particular attention to possible approaches to their management. Patients with COPD may also have other extrapulmonary effects such as hormonal abnormalities that could probably be corrected, but less is known about them. COPD, therefore, should be regarded as a systemic disorder. Its systemic manifestations should not be overlooked in the overall care of the patient, because there are important ways in which they can be addressed.

Separation of alveolar surfactant into subtypes. A comparison of methods.

Alveolar surfactant is known to exist in several morphologic forms or subtypes which have been separated from bronchoalveolar lavage fluid (BAL) by two types of methods-differential centrifugation (DC) and equilibrium buoyant density gradient centrifugation (EBDC). DC separates BAL into large aggregates (LA) and small aggregates (SA); EBDC separates BAL into three peaks called ultraheavy (UH), heavy (H), and light (L). We compared these two separation methods by subjecting replicates of the same pools of BALF from groups of mice to DC and EBDC in parallel assays. We found that each method was highly internally consistent, but that the amount of phospholipid in the LA fraction of DC was consistently and substantially less (by 33 to 43%) than that found in the UH + H fractions of EBDC. This appeared to be due to failure of DC to sediment all of the phospholipid that banded as UH or H in EBDC despite adjustments in the time and g-force of DC. In experiments where differentially labeled purified H and L subtypes were subjected to DC over a wide range of g-force and time conditions, cross-contamination of the DC pellet and supernatant with heterologous subtypes was always present (4 to 33% cross-contamination). Addition of extraneous serum proteins to the BAL, as a model of lung damage, resulted in further inconsistencies in DC but not EBDC. Investigators may wish to bear these considerations in mind when planning or interpreting the results of experiments bearing on surfactant subtype analysis.

Is dipalmitoylphosphatidylcholine a substrate for convertase?

Convertase has homology with carboxylesterases, but its substrate(s) is not known. Accordingly, we determined whether dipalmitoylphosphatidylcholine (DPPC), the major phospholipid in surfactant, was a substrate for convertase. We measured [(3)H]choline release during cycling of the heavy subtype containing [(3)H]choline-labeled DPPC with convertase, phospholipases A(2), B, C, and D, liver esterase, and elastase. Cycling with liver esterase or peanut or cabbage phospholipase D produced the characteristic profile of heavy and light peaks observed on cycling with convertase. In contrast, phospholipases A(2), B, and C and yeast phospholipase D produced a broad band of radioactivity across the gradient without distinct peaks. [(3)H]choline was released when natural surfactant containing [(3)H]choline-labeled DPPC was cycled with yeast phospholipase D but not with convertase or peanut and cabbage phospholipases D. Similarly, yeast phospholipase D hydrolyzed [(3)H]choline from [(3)H]choline-labeled DPPC after incubation in vitro, whereas convertase, liver esterase, or peanut and cabbage phospholipases D did not. Thus convertase, liver esterase, and plant phospholipases D did not hydrolyze choline from DPPC either on cycling or during incubation with enzyme in vitro. In conclusion, conversion of heavy to light subtype of surfactant by convertase may require a phospholipase D type hydrolysis of phospholipids, but the substrate in this reaction is not DPPC.

Effects of salmeterol on arterial blood gases in patients with stable chronic obstructive pulmonary disease. Comparison with albuterol and ipratropium.

Administration of beta-adrenergic agonist bronchodilators to patients with airways obstruction commonly results in transient decreases in Pa(O(2)) levels despite bronchodilation, an effect that has been attributed to these drugs' pulmonary vasodilator action. We compared the acute effects on gas exchange of salmeterol with those of albuterol and the anticholinergic agent ipratropium in 20 patients with stable chronic obstructive pulmonary disease (COPD). Each agent was given in recommended dosage on separate days in a double-blind, crossover format, and the patients' arterial blood gases (ABGs) were measured at baseline and at intervals to 120 min. Small but statistically significant declines in Pa(O(2)), the primary outcome variable, were found after administration of both salmeterol and albuterol. The decline in PaO2 after salmeterol was of lesser magnitude but was more prolonged than that after albuterol, the greatest mean change being -2.74 +/- 0.89 mm Hg (mean +/- SEM) at 30 min after salmeterol, and -3.45 +/- 0.92 mm Hg at 20 min after albuterol. Following ipratropium, the corresponding change was -1.32 +/- 0.85 mm Hg at 20 min. These declines, which were almost entirely attributable to increases in the alveolar-arterial difference in oxygen tension Delta(A-a)DO2 tended to be more marked in subjects with higher baseline PaO2 values. No subject experienced a decline in PaO2 to levels below 59 mm Hg. There were no significant differences among the three drugs studied. We conclude that despite small decreases in PaO2 after each of the three drugs, the declines were small transient, and of doubtful clinical significance.

Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group.

BACKGROUND AND METHODS: Although their clinical efficacy is unclear and they may cause serious adverse effects, systemic glucocorticoids are a standard treatment for patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD). We conducted a double-blind, randomized trial of systemic glucocorticoids (given for two or eight weeks) or placebo in addition to other therapies, for exacerbations of COPD. Most other care was standardized over the six-month period of follow-up. The primary end point was treatment failure, defined as death from any cause or the need for intubation and mechanical ventilation, readmission to the hospital for COPD, or intensification of drug therapy. RESULTS: Of 1840 potential study participants at 25 Veterans Affairs medical centers, 271 were eligible for participation and were enrolled; 80 received an eight-week course of glucocorticoid therapy, 80 received a two-week course, and 111 received placebo. About half the potential participants were ineligible because they had received systemic glucocorticoids in the previous 30 days. Rates of treatment failure were significantly higher in the placebo group than in the two glucocorticoid groups combined at 30 days (33 percent vs. 23 percent, P=0.04) and at 90 days (48 percent vs. 37 percent, P=0.04). Systemic glucocorticoids (in both groups combined) were associated with a shorter initial hospital stay (8.5 days, vs. 9.7 days for placebo, P=0.03) and with a forced expiratory volume in one second that was about 0.10 liter higher than that in the placebo group by the first day after enrollment. Significant treatment benefits were no longer evident at six months. The eight-week regimen of therapy was not superior to the two-week regimen. The patients who received glucocorticoid therapy were more likely to have hyperglycemia requiring therapy than those who received placebo (15 percent vs. 4 percent, P=0.002). CONCLUSIONS: Treatment with systemic glucocorticoids results in moderate improvement in clinical outcomes among patients hospitalized for exacerbations of COPD. The maximal benefit is obtained during the first two weeks of therapy. Hyperglycemia of sufficient severity to warrant treatment is the most frequent complication.

Influence of phospholipid composition on the properties of reconstituted surfactants.

The influence of phospholipids on the ultrastructure and metabolism of reconstituted surfactants has not been well defined. The aim of this study was to determine if changes in the phospholipid composition of reconstituted surfactants altered their biophysical properties, ultrastructure, and conversion to light subtype by cycling. We prepared various surfactants containing radiolabeled dipalmitoylphosphatidylcholine ([14C]DPPC). The addition of phosphatidylglycerol (PG) or dipalmitoylphosphatidic acid (PA) to DPPC increased conversion to light subtype. In contrast, the addition of dipalmitoylphosphatidylglycerol (DPPG) to DPPC markedly reduced conversion to light subtype on cycling. DPPC and DPPC+PG produced large liposomes ( approximately 1,000 nm), whereas DPPC+PA or DPPC+DPPG formed multilamellar membranes. Mixtures of DPPC and PA were highly surface active in vitro, whereas the surface activity of DPPC+DPPG was similar to that of DPPC. In conclusion, the ultrastructure, metabolism, and surface active properties of DPPC+PG mixtures were influenced markedly by alterations in the fatty acid composition or polar head group of PG.

Efficacy of salmeterol xinafoate in the treatment of COPD.

STUDY OBJECTIVES: To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled beta2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD. DESIGN: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial. SETTING: Multiple sites at clinics and university medical centers throughout the United States. PATIENTS: Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65% predicted and no clinically significant concurrent disease. INTERVENTIONS: Comparison of inhaled salmeterol (42 microg twice daily), inhaled ipratropium bromide (36 microg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks. RESULTS: Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments. CONCLUSIONS: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD.

Molecular cloning, characterization, and differential expression pattern of mouse lung surfactant convertase.

We recently reported the purification and partial amino acid sequence of "surfactant convertase," a 72-kDa glycoprotein involved in the extracellular metabolism of lung surfactant (S. Krishnasamy, N. J. Gross, A. L. Teng, R. M. Schultz, and R. Dhand. Biochem. Biophys. Res. Commun. 235: 180-184, 1997). We report here the isolation of a cDNA clone encoding putative convertase from a mouse lung cDNA library. The cDNA spans a 1,836-bp sequence, with an open reading frame encoding 536 amino acid residues in the mature protein and an 18-amino acid signal peptide at the NH2 terminus. The deduced amino acid sequence matches the four partial amino acid sequences (68 residues) that were previously obtained from the purified protein. The deduced amino acid sequence contains an 18-amino acid residue signal peptide, a serine active site consensus sequence, a histidine consensus sequence, five potential N-linked glycosylation sites, and a COOH-terminal secretory-type sequence His-Thr-Glu-His-Lys. Primer-extension analysis revealed that transcription starts 29 nucleotides upstream from the start codon. Northern blot analysis of RNA isolated from various mouse organs showed that convertase is expressed in lung, kidney, and liver as a 1,800-nucleotide-long transcript. The nucleotide and amino acid sequences of putative convertase are 98% homologous with mouse liver carboxylesterase. It thus may be the first member of the carboxylesterase family (EC 3.1.1.1) to be expressed in lung parenchyma and the first with a known physiological function.

Protein-lipid interactions and enzyme requirements for light subtype generation on cycling reconstituted surfactant.

Surfactant convertase is required for conversion of heavy density (H) natural surfactant to light density (L) subtype during cycling in vitro, a technique that reproduces surfactant metabolism. To study mechanisms of H to L conversion, we prepared liposomes of dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG), or the phospholipids (PL) in combination with either surfactant protein A (SP-A), surfactant protein B (SP-B), or both SP-A and SP-B. Phospholipids alone showed time-dependent conversion from heavy to light subtype on cycling in the absence of convertase, which was decreased by adding SP-B, but not SP-A, to phospholipids (p < 0.01 for PL+SP-B, or PL+SP-A+SP-B vs. PL, or PL+SP-A). The ultrastructure, surface activity, buoyant density, and L subtype generation on cycling PL+SP-A+SP-B with partially purified convertase or with phospholipase D were similar to those of natural TM. In conclusion, a reconstituted surfactant mimics the behavior of natural surfactant on cycling, and reveals that interaction of SP-B with phospholipids decreases L subtype generation. In addition, esterase/ phospholipase D activity is required for conversion of heavy to light subtype on cycling.

Surfactant convertase action is not essential for surfactant film formation.

A serine-active enzyme, "surfactant convertase", is required for the conversion of surfactant from the tubular myelin (TM) form to the small vesicular (SV) form. This transformation involves at least two steps, the conversion of TM to a surface-active film at the air-fluid interface and the reorientation of the film into the surface-inactive SV form; we asked if convertase was required for the first of these steps. Rat and mouse TMs were pretreated with diisopropyl fluorophosphate (DFP) to inactivate endogenous convertase activity or with vehicle and then were analyzed for their ability to lower surface tension in vitro as an index of the conversion of TM to a surface film. DFP pretreatment did not alter the ability of TM preparations to lower surface tension, as assessed by pulsating bubble, and it did not affect the behavior of TM in a surface balance. In an experiment designed to test the ability of TM to feed a surface film to exhaustion, TMs that had been pretreated with DFP or vehicle performed similarly. These experiments show that convertase activity is not required for the conversion of TM to a monolayer and suggest, instead, that convertase acts at a post surface film stage.

Lung "surfactant convertase" is a member of the carboxylesterase family.

The extracellular conversion of lung surfactant from tubular myelin to the small vesicular form has previously been shown to require a serine-active enzyme called "surfactant convertase." In the present study, a 72kD serine-active enzyme previously identified in mouse lung alveolar lavage and having convertase activity was partially sequenced. Sixty-eight residues obtained from amino acid sequencing of this protein show that it is a new member of the mouse carboxylesterase family (EC 3.1.1.1). The 72kD lung protein also has esterase activity. A commercial esterase of the same family was able to reproduce surfactant convertase bioactivity in vitro, unlike several serine proteinases previously tested. We conclude that surfactant convertase is a carboxylesterase which mediates a biochemical step in the extracellular metabolism of surfactant.