High-average-power femtosecond fiber chirped-pulse amplification system.

Efficient generation of 76-W average power of 400-fs pulses at 75-MHz repetition rate by use of a diode-pumped ytterbium-doped double-clad fiber-based chirped-pulse amplification system is demonstrated. The key element in the system is a diffraction grating compressor consisting of highly efficient transmission gratings in fused silica, allowing recompression at this high power level.

Effective suppression of vancomycin-resistant Enterococcus species in asymptomatic gastrointestinal carriers by a novel glycolipodepsipeptide, ramoplanin.

Nosocomial bloodstream infections due to vancomycin-resistant enterococci (VRE) are associated with increased morbidity rates, mortality rates, and hospitalization costs. Gastrointestinal carriage of VRE is an important risk factor for subsequent infections. This 3-arm, phase II, double-blinded, randomized, multicenter, placebo-controlled study evaluated the safety and efficacy of oral ramoplanin (a novel, nonabsorbed glycolipodepsipeptide) versus placebo for suppression of gastrointestinal VRE colonization. Sixty-eight patients who were colonized with VRE were enrolled and received 2 daily doses of ramoplanin (100 mg or 400 mg) or placebo orally for 7 days. The primary end point was the proportion of persons per group from whom VRE were not recovered (VRE-free) on days 7, 14, and 21 after screening. After treatment, VRE-free status was as follows: day 7, none of the 20 patients in the placebo group, and 17 of 21 (P<.001) and 18 of 20 (P<.001) in the 100-mg and 400-mg ramoplanin groups, respectively; on day 14, 2 of 20 patients in the placebo group, and 6 of 21 (P=.134) and 7 of 17 (P=.028), in the 100-mg and 400-mg ramoplanin groups, respectively. By day 21, there were no differences between treatment groups. Adverse events were similar for all treatment groups. Ramoplanin was safe and effective in temporarily suppressing gastrointestinal VRE carriage.

Assessment of various topical oral formulations by bone marrow transplant recipients.

Topical approaches to management of oral mucositis have the advantages of high local concentration and limited or no systemic absorption, reducing the risk of systemic complications. The acceptability of topical therapies in cancer patients has not been evaluated. Thirty-eight transplant patients assessed the acceptability of three formulations (rinse, thin gel, thick gel) of a new compound developed to prevent oral mucositis. The rinse was selected as the most acceptable formulation. The thick gel received the lowest rating. Consistency was a major determinant of overall acceptability. A neutral taste was desirable for most participants. Room temperature of the formulation was rated as completely acceptable. Most participants would be willing to use the rinse or thin gel several times per day, to retain each dose in the oral cavity for up to 5 min, and to swallow it. The support of caregivers may be needed to achieve compliance with such regimens.

Patient reports of complications of bone marrow transplantation.

In recent years, significant improvements have been made in the management of neutropenia and thrombocytopenia and other potentially life-threatening complications of ablative chemotherapy. While these complications are of particular concern to physicians, patients receiving ablative therapy for bone marrow or blood stem cell transplants are often troubled by other side effects such as nausea, vomiting, diarrhea and mouth sores. The purpose of the study was to gain a better understanding of patients' experiences while undergoing a transplant. The same professional medical interviewer conducted in-depth interviews with 38 subjects (10 men, 28 women; mean age 46.9 years) who had received ablative therapy for bone marrow and/or peripheral blood stem cell transplants. Participants were consecutively identified through physician and patient referrals, cancer and BMT patient support groups, and newspaper advertisements. Twenty-eight patients (74%) received autologous stem cell transplants and 10 patients (26%) received allogeneic transplants. Participants reported mouth sores, nausea and vomiting, diarrhea, and fatigue as the most troubling side effects of their transplants. Mouth sores were selected as the single most debilitating side effect (42%), followed by nausea and vomiting (13%). Many patients mentioned that mouth sores made it difficult or impossible to eat (n = 23), swallow (n = 21), drink (n = 17), and/or talk (n = 8). Twenty patients reported pain in the mouth, throat, and/or esophagus. Two-thirds (66%) of patients reported receiving opioid analgesics, most frequently morphine, to relieve oral pain. For many, opioids caused incapacitating side effects, including hallucinations, a feeling of loss of control and a decrease in mental acuity. Patients receiving ablative chemotherapy identify oral mucositis as a significant cause of suffering and morbidity. Effective interventions to alleviate this complication are urgently needed.

Safety of repeated intermittent courses of aerosolized recombinant human deoxyribonuclease in patients with cystic fibrosis.

OBJECTIVES: To determine the effect of repeated doses of aerosolized recombinant human deoxyribonuclease (rhDNase) on the development of anti-rhDNase antibodies, acute allergic reactions, and pulmonary function in patients with cystic fibrosis. DESIGN: A multicenter, open-label study in which 184 patients received 10 mg aerosolized rhDNase twice a day for 14 days followed by a 14-day washout period for a total of 6 treatment cycles. Serial determinations of anti-rhDNase antibodies and pulmonary functions were performed. RESULTS: Detectable anti-rhDNase antibodies developed in 16 (8.7%) patients. These patients had no changes in their symptoms from the time they entered the trial. Antibodies detected were all of the IgG isotype. Increases in both forced expired volume in 1 second and forced vital capacity were noted from the beginning to the end of each cycle of treatment returning to baseline during the off-treatment period of each cycle. Seropositivity to rhDNase was not associated with allergic reactions and had no relationship on improvement in pulmonary function. CONCLUSIONS: Development of anti-rhDNase antibodies occurred in a small number of patients and was not associated with side effects. Intermittent administration of rhDNase for 24 weeks to patients with cystic fibrosis was well tolerated and was not associated with anaphylaxis in any patient. Pulmonary function improved significantly during the 14-day cycles while rhDNase was administered and returned to baseline when rhDNase was discontinued.

Aerosolized recombinant human DNase in hospitalized cystic fibrosis patients with acute pulmonary exacerbations.

The goal of this study was to evaluate the safety and efficacy of recombinant human DNase (rhDNase) in hospitalized patients with cystic fibrosis (CF) experiencing acute pulmonary exacerbations. Eighty patients with documented CF were enrolled at 11 CF centers when admitted for antibiotic therapy. Patients were at least 5 yr old with a forced vital capacity (FVC) > or = 35% of predicted and an oxygen saturation > or = 90% on a fraction of inspired oxygen (FIO2) < 0.5. Patients were randomized to receive rhDNase 2.5 mg in 2.5 ml excipient twice a day (n = 43) or 2.5 ml excipient alone twice daily (n = 37) along with conventional treatment for exacerbations. Administration of rhDNase was not associated with acute adverse events or deaths, and no patients experienced allergic or anaphylactic reactions. Although forced expiratory volume in one second (FEV1) and FVC improved in both treatment groups during the double-blind period, there were no statistically significant differences in the mean change from baseline in FEV1 or FVC between the two groups. rhDNase therapy is safe and well tolerated in CF patients with acute exacerbations requiring hospitalization, but the study did not demonstrate a statistically significant therapeutic effect of rhDNase when added to a regimen of antibiotics and chest physical therapy.

Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis.

We tested the hypothesis that recombinant human deoxyribonuclease 1 (rhDNase) reduces airflow obstruction and improves mucociliary clearance in patients with cystic fibrosis (CF), and that improvements seen in FEV1 and FVC after rhDNase treatment are independent of chest physical therapy (CPT). CF patients inhaled placebo (10 patients) or 2.5 mg rhDNAse aerosol (10 patients) twice a day for six consecutive days. Compared with baseline, there were no statistically significant differences between the two study groups by Day 6 for indices of airflow obstruction obtained from gamma-camera images of the right lung following inhalation of 99mTc aerosol, or for mucociliary clearance or the rate of clearance of the radioaerosol, quantified over a 6-h period. By Day 6, FEV1 and FVC were significantly higher in the rhDNase-treated group than in the placebo group, increasing by an average of 9.4 +/- 3.5% and 12.7 +/- 2.6%, respectively, as compared with a decrease of 1.8 +/- 1.7% and an increase of 0.4 +/- 1.1%, respectively (p < 0.05). There was no significant change in the FEV1/FVC ratio on Day 6 (0.68 +/- 0.05) compared with baseline (0.70 +/- 0.05) in the rhDNase group. On Day 6, FEV1 and FVC decreased after CPT in both study groups, but the decreases were not significant. Our results indicate that aerosolized rhDNase improves FEV1 and FVC independent of CPT. We were unable to demonstrate that rhDNase reduces airflow obstruction or improves mucociliary clearance.

Comparison of three jet nebulizer aerosol delivery systems used to administer recombinant human DNase I to patients with cystic fibrosis. The Pulmozyme rhDNase Study Group.

STUDY OBJECTIVE: To compare the degree of improvement in pulmonary function achieved with recombinant human DNase I (rhDNase) administered by three different aerosol delivery systems: DeVilbiss Pulmo-Aide compressor with the Marquest Acorn II nebulizer, the Hudson T Up-draft nebulizer, and the Pari LC Jet Plus nebulizer with the Pari Inhalier Boy compressor. These produce similar aerosols in vitro in terms of size distribution and activity of delivered rhDNase. STUDY DESIGN: Multicenter, randomized, open-label, parallel-group comparison of changes from baseline in pulmonary function variables in each test group. Patients were treated with rhDNase (2.5 mg bid) for 15 days, administered with three different aerosol delivery systems. SETTING: Outpatient clinics at 26 sites in the United States. PATIENTS: 397 patients > 5 years of age with cystic fibrosis and baseline forced vital capacity (FVC) values between 40 and 70% of predicted values. RESULTS: All three nebulizers gave comparable improvements in pulmonary function. FEV1 increased by an average of 13.2 to 14.1%, FVC by 10.9 to 11.8% and forced midexpiratory flow (FEF25-75) by 16.5 to 17.1%. No unusual or unexpected adverse events were reported other than those that would be expected in patients with cystic fibrosis. CONCLUSIONS: Recombinant human DNase I produced a similar magnitude of improvement in the pulmonary function of patients with cystic fibrosis when the drug was administered using three different types of nebulizer systems with similar in vitro delivery and safety characteristics.

Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment.

Chronic pulmonary infection is the major cause of morbidity and mortality in cystic fibrosis (CF). Recombinant human deoxyribonuclease (rhDNase) in vitro has been shown to dramatically reduce the viscoelasticity of the sputum from CF patients. Phase II and III clinical trials have shown the drug to be safe, and that patients with a forced vital capacity (FVC) of > 40% predicted show an improvement in pulmonary function when receiving rhDNase. The current study evaluates the safety and efficacy of rhDNase in the most severly ill CF patients (FVC < 40% predicted). A double-blind, randomized, placebo-controlled trial in which patients received either 2.5 mg rhDNase twice daily or placebo for a period of 14 days followed by a 6 month open extension period (OEP) is reported. Seventy patients were recruited for the double-blind study, and 64 entered the OEP of whom 38 completed. During the OEP, all patients received 2.5 mg rhDNase twice daily. In both the double-blind period and the OEP the drug appeared to be safe. During the double-blind study, forced expiratory volume in one second (FEV1) and FVC improved in both groups but there was no statistically significant difference between the groups. In the OEP, there was mean improvement in percentage predicted FEV1 and FVC, 9 and 18%, respectively, for all patients participating. In conclusion, DNase is safe when administered in conjunction with a rigorous regimen of chest physiotherapy to severely ill patients (FVC < 40% predicted) with CF. The double-blind, 14 day study showed no significant improvement in pulmonary function but some patients may have improved after longer administration of rhDNase.

Effects of recombinant human DNase therapy on healthcare use and costs in patients with cystic fibrosis.

OBJECTIVE: To assess the effects of recombinant human DNase (rhDNase) therapy on the cost of treating respiratory tract infections (RTIs) in patients with cystic fibrosis. DESIGN: We prospectively documented the use of healthcare services among 968 patients with cystic fibrosis who participated in a recent Phase III double-blind, multicenter, clinical trial in which patients were assigned randomly to receive either rhDNase 2.5 mg once daily, rhDNase 2.5 mg twice daily, or placebo. All patients were followed for 24 weeks. Data from secondary sources were used to estimate a total cost of RTI-related care (excluding the cost of study therapy) for each trial participant, based on observed levels of resource use. MAIN OUTCOME MEASURES: Number of RTI-related hospital admissions, days of RTI-related outpatient antibiotic therapy (intravenous and oral), and total costs of RTI-related care (excluding the cost of study therapy). RESULTS: Patients randomized to receive rhDNase once daily averaged 0.15 fewer RTI-related hospital admissions (0.41 vs 0.56 for placebo; p < 0.05) and 1.5 fewer days of RTI-related outpatient intravenous antibiotic therapy (2.9 vs 4.4; p < 0.05). Patients randomized to receive rhDNase twice daily had 0.14 fewer hospital admissions (p < 0.01), but no reduction in outpatient intravenous antibiotic therapy. Compared with placebo, the cost of treating RTIs over 24 weeks was $814-1682 less among patients receiving rhDNase. CONCLUSIONS: rhDNase therapy reduced the costs of treating RTIs in patients with cystic fibrosis; assuming once-daily dosing, these savings would offset about one-third of the cost of such therapy.

Medium term treatment of stable stage cystic fibrosis with recombinant human DNase I.

BACKGROUND: A phase II multicentre double blind placebo controlled study in 1993 showed that short term treatment (10 days) with recombinant human DNase I (rhDNase) was safe and improved pulmonary function in patients with cystic fibrosis with stable stage lung disease. A six month open label treatment study was conducted in some of the patients who participated in the short term study to assess the medium term effects of rhDNase. METHODS: Patients who completed the phase II study and were stable for 14 days prior to treatment were eligible. They were treated with rhDNase 2.5 mg twice daily for six months and reviewed at regular intervals to assess safety and efficacy. RESULTS: Fifty nine patients (31M,28F) of age range 16-55 years were recruited. Mean baseline values for forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were 41.5% and 72.4% of predicted, respectively. The mean increase in FEV1 over the first month of treatment was 13.1% (range 12-14.1%) and then stabilised at 6.2% (4.6-7.8%) for the subsequent five months. FVC was similarly improved. Administration of rhDNase improved the severity of dyspnoea, cystic fibrosis related symptoms, and the modified Taussig/NIH score (not statistically significant). Fifty seven of the 59 patients completed the study; two died from progression of their pulmonary disease unrelated to treatment with rhDNase. The adverse events and intercurrent illnesses were no different from those expected in a cystic fibrosis population. Pharyngitis was the only possible drug related adverse event which occurred at least once in 14% of patients during the six month period. CONCLUSIONS: Administration of rhDNase was safe, well tolerated, and improved pulmonary function in patients with cystic fibrosis. When rhDNase was stopped at day 169 there was a deterioration in pulmonary function and dyspnoea score.

[Risk of cataract surgery in patients with myopia. A prospective Danish multicenter study with special reference to a complication]. / Risiko ved operation for grå staer hos naersynede. En prospektiv dansk multicenterundersøgelse med soerligt henblik på komplikationen nethindeløsning.

A prospective Danish multicentre study was conducted to evaluate the incidence of retinal detachment after cataract extraction in myopic eyes (axial length, > or = 25.5 mm). Two hundred and forty-seven cataract extractions in myopic eyes were reported during a period of 13 months. Two hundred and forty-one eyes underwent extracapsular and six eyes intracapsular cataract extraction. The mean follow-up time for 158 eyes was seven months (ranging from 1-30 months). In five cases a retinal detachment was observed, one case was probably present preoperatively, this person had undergone intracapsular cataract extraction. The incidence of retinal detachment was thus 1.62-2.02% in the total material and 1.66% in eyes operated with extracapsular cataract extraction.

Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.

BACKGROUND: Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, which results in recurrent, symptomatic exacerbations. The viscoelasticity of the secretions can be reduced in vitro by recombinant human deoxyribonuclease I (rhDNase), a bioengineered copy of the human enzyme. METHODS: We performed a randomized, double-blind, placebo-controlled study to determine the effects of once-daily and twice-daily administration of rhDNase on exacerbations of respiratory symptoms requiring parenteral antibiotics and on pulmonary function. A total of 968 adults and children with cystic fibrosis were treated for 24 weeks as outpatients. RESULTS: One or more exacerbations occurred in 27 percent of the patients given placebo, 22 percent of those treated with rhDNase once daily, and 19 percent of those treated with rhDNase twice daily. As compared with placebo, the administration of rhDNase once daily and twice daily reduced the age-adjusted risk of respiratory exacerbations by 28 percent (P = 0.04) and 37 percent (P < 0.01), respectively. The administration of rhDNase once daily and twice daily improved forced expiratory volume in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. None of the patients had anaphylaxis. Voice alteration and laryngitis were more frequent in the rhDNase-treated patients than in those receiving placebo but were rarely severe and resolved within 21 days of onset. CONCLUSIONS: In patients with cystic fibrosis, the administration of rhDNase reduced but did not eliminate exacerbations of respiratory symptoms, resulted in slight improvement in pulmonary function, and was well tolerated.

[Glaucoma blindness in Denmark]. / Glaukomblindhed i Danmark.

The prevalence and the incidence of glaucoma blindness in Denmark was evaluated by examining all registration forms of persons > or = 50 years of age admitted to the Danish Association of the Blind (DAB) between 1955 and 1987 with glaucoma as main cause of blindness. In 1987, 6.7% of DAB-members > or = 50 years suffered from blindness caused at least partially by glaucoma, equivalent to an estimated prevalence of 45 per 100,000 of the Danish population > or = 50 years. The estimated annual incidence of blindness due to glaucoma was seven per 100,000 > or = 65 years, and in an equal number of patients glaucoma was a contributory cause of blindness. The incidence of glaucoma blindness was decreasing in the younger age groups (< 65 years) throughout the study period. Glaucoma blindness seems to occur at a later age now than earlier, leaving the patients blind for a shorter time. The proportion of glaucoma blindness in the glaucoma population was estimated to be 4-5%.

Reduction in intensity of Pneumocystis carinii pneumonia in mice by aerosol administration of gamma interferon.

Pneumocystis carinii pneumonia in patients with AIDS may result from impaired local release of gamma interferon from lung lymphocytes and subsequent failure of macrophage activation. We tested this hypothesis with mice rendered immunodeficient by selective depletion of CD4+ lymphocytes and inoculated intratracheally with P. carinii. After aerosol administration of recombinant murine gamma interferon, the intensity of P. carinii infection in these mice was reduced in comparison with that in mice not treated with gamma interferon. Histologic scoring of lung tissue did not reveal additional pulmonary inflammation attributable to gamma interferon. Aerosol administration of gamma interferon may reduce the intensity of P. carinii infection by augmentation of host defense, despite persistent CD4+ lymphocyte depletion.

Intravascular IL-8. Inhibitor of polymorphonuclear leukocyte accumulation at sites of acute inflammation.

IL-8 has been characterized primarily as a polymorphonuclear leukocyte (PMN) chemoattractant and proinflammatory mediator. Recently, we have reported that [Ala-IL-8]77 is secreted by activated cultured human endothelial cells and can function as a potent inhibitor of PMN adhesion to these monolayers. The pathophysiologic relevance of this in vitro observation was examined by determining the effects of intravascular or extravascular administration of IL-8 on PMN emigration at sites of acute inflammation in the skin of NZW rabbits. An i.v. bolus of [Ala-IL-8]77 (12 micrograms/kg) produced a marked and selective reduction of circulating PMN within 3 min, which returned toward preinjection levels within 30 min, and subsequently exceeded this level. A similar response was observed for circulating radiolabeled PMN, and gamma-scintigraphy determined that the lungs were the primary site of leukosequestration. During the 30- to 150-min interval after i.v. infusion of [Ala-IL-8]77, PMN emigration into acute inflammatory sites, elicited by various chemoattractants or cytokines, was significantly reduced, as judged histologically and quantitated with 51Cr-labeled PMN and myeloperoxidase measurements. Intravenous administration of [Ser-IL-8]72 yielded similar results. This inhibitory effect of i.v. IL-8 was transient and reinducible and did not reflect a suppression of the responsiveness of circulating PMN to chemoattractants. Intradermal injections of [Ala-IL-8]77 or [Ser-IL-8]72 induced dose-dependent PMN accumulation, which also was significantly reduced by i.v. administration of either form of IL-8. These results indicate that i.v. IL-8 can function as a PMN-directed leukocyte adhesion inhibitor and suggest that local secretion of IL-8 by activated endothelium may differentially modulate leukocyte-endothelial interactions at sites of acute inflammation.

The pattern of lung injury induced after pulmonary exposure to tumor necrosis factor-alpha depends on the route of administration.

TNF-alpha is a protein elaborated by monocytes and macrophages in response to endotoxin. The in vivo consequences of TNF-alpha elaboration have been examined extensively after intravenous administration of TNF-alpha. Substantially less is known about the effects of TNF-alpha that may be generated locally by resident tissue phagocytes. We investigated the direct effects of TNF-alpha on lung tissue by administering large amounts of human TNF-alpha directly to the lung, either as an aerosol or as an intratracheal bolus. Rats were exposed to an aerosol containing several concentrations of TNF-alpha, resulting in retention of significant quantities of TNF-alpha. The histologic response to inhaled TNF-alpha was characterized by adherence of leukocytes to venular endothelium, endothelial cell disruption, and bronchovascular edema. After aerosol administration, however, there was no evidence of alveolar inflammation or edema. In contrast, intravenous administration of large amounts of human TNF-alpha, at a dose that produced a lung content of TNF-alpha similar to that produced after high-concentration aerosol exposure, resulted in severe alveolar injury and edema. Intravenous administration of TNF-alpha did not result in the bronchovascular changes seen after inhalation. To ensure that sufficient quantities of TNF-alpha were being delivered to the lung, TNF-alpha was given as an intratracheal bolus to rats. This led to measurable absorption, but the spectrum and severity of lung injury was similar to the group that received TNF-alpha as an aerosol. We conclude that in rats, the pulmonary response to the injurious effects of TNF-alpha differ, depending on whether the TNF-alpha is delivered to the air or blood side of the alveolar capillary barrier.

Immunomodulatory and toxic effects of free and liposome-encapsulated tumor necrosis factor alpha in rats.

Tumor necrosis factor alpha has potent immunomodulatory and antitumor activity, but its therapeutic applications may be limited by its significant host toxicity. We showed that liposome-encapsulated recombinant human tumor necrosis factor alpha (rHuTNF-alpha) retained full anticellular activity in vitro. We then assessed the immunomodulatory and toxic effects of two different doses of i.v. free or liposome-encapsulated rHuTNF-alpha in normal rats. Both free and liposome-encapsulated rHuTNF-alpha significantly enhanced alveolar macrophage- and blood monocyte-mediated interleukin 1 release and tumor cell lysis, as well as natural killer cell cytotoxicity, when compared to buffer-treated controls. However, administration of rHuTNF-alpha in liposomes substantially reduced tumor necrosis factor alpha-mediated toxicity. Animals receiving liposome-encapsulated rHuTNF-alpha showed significantly less tissue injury, gastric retention, and circulating leukocyte shifts than animals receiving free rHuTNF-alpha. In addition, liposome-based delivery significantly increased lung and liver uptake of rHuTNF-alpha. Therefore, liposome-encapsulated rHuTNF-alpha retains immunomodulatory activity, significantly reduces toxic inflammatory effects, and may allow targeting of tumor necrosis factor alpha to selected organs after i.v. administration.