Ablation of the cornea by using a low-energy excimer laser

We describe a new multipurpose method for corneal refractive surgery by using a focused excimer laser beam, which allows the application of a small, compact low-energy excimer laser. It is possible to ablate any area desired in the cornea without masking by scanning the focused beam. The ablation depths in freshly enucleated swine eyes were measured in relation to the number of laser pulses (at fixed fluence) and the pulse fluence at wavelengths = 248 nm and =193 nm. The irradiation conditions were investigated to obtain smooth ablation of the corneal material over an area of about 1 cm². The experiments show that smooth ablation is obtained when the ratio of the excimer laser beam spot diameter on the corneal surface and the displacement for one scanning step is given by a whole number. A simple model based on rectangular beam profiles is presented to exemplify this.     

Analysis of Drug/Plasma Protein Interactions by Means of Asymmetrical Flow Field-Flow Fractionation

Purpose. The applicability of Asymmetrical Flow Field-Flow Fractionation (Asymmetrical Flow FFF) as an alternative tool to examine the distribution of a lipophilic drug (N-Benzoyl-staurosporine) within human plasma protein fractions was investigated with respect to high separation speed and loss of material on surfaces due to adsorption. Methods. Field-Flow Fractionation is defined as a group of pseudo-chromatographic separation methods, where compounds are separated under the influence of an externally applied force based on differences in their physicochemical properties. This method was used to separate human plasma in its protein fractions. The drug distribution in the fractions was investigated by monitoring the fractionated eluate for drug content by fluorescence spectroscopy. Results. Human plasma was separated into human serum albumin (HSA), high density lipoprotein (HDL), ₂-macroglobulin and low density lipoprotein (LDL) fractions in less than ten minutes. Calibration of the system and identification of the individual fractions was performed using commercially available protein reference standards. The influence of membrane type and carrier solution composition on the absolute recovery of N-Benzoyl-staurosporine and fluorescein-isothio-cyanate-albumin (FITC-albumin) was found to be quite significant. Both factors were optimized during the course of the investigations. N-Benzoyl-staurosporine was found to be enriched in the fraction containing HSA. Conclusions. If experimental conditions are thoroughly selected and controlled to suppress drug and plasma protein adsorption at the separation membrane, Asymmetrical Flow FFF shows high recoveries and fast separation of human plasma proteins, and can be a reliable tool to characterize drug / plasma protein interactions. For analytical purposes it has the potential to rival established technologies like ultracentrifugation in terms of ease-of-use, precision, and separation time.     

Two Types of Health Care Systems and Their Influence on the Introduction of Perinatal Care: An Epidemiological Twin Model in Berlin from 1950 to 1990

Objectives: When perinatal medicine emerged as a new medical discipline in the 1960s, Berlin was as one of the world's leading centers. During that time, the city was separated into two parts, each fostering its own health care system. After the destruction of the Berlin Wall, it was possible to speak with the citizens of East Berlin and to access their database systems. This created the singular opportunity to objectively compare the development of perinatal care in both parts of Berlin. Methods: Rates of maternal, perinatal, and infant mortality as well as the rate of preterm deliveries were evaluated over time and between East and West Berlin. The timing of introduction of 20 specific perinatal interventions was evaluated across 18 hospitals with more than 500 deliveries (11 in West Berlin and 7 in East Berlin). Interviews were conducted with 100 gynecologists, 100 midwives, and 100 women who had recently delivered their first child from each side of the city regarding their opinions of the importance of these interventions for the quality of perinatal medicine and how they would distribute a budget to improve maternity care. Results: Maternal, perinatal, and infant mortality decreased in both parts of Berlin until 1990 (p<0.0001), without significant differences between East and West Berlin, though the preterm delivery rate was slightly lower in East Berlin compared with West Berlin (p<0.06). Some new clinical techniques and treatments—such as cardiotocography, ultrasound, tocolytic therapy, and peridural anesthesia—were introduced earlier in West Berlin. In contrast, certain public health measures—such as maternal transport, screening programs for diabetes, and support of breastfeeding—were introduced much earlier in East Berlin. There were significant differences between the beliefs of gynecologists, midwives, and mothers in East and West Berlin. In general, citizens of East Berlin were more enthusiastic about technological medical advances, whereas citizens of West Berlin were more supportive of public health and alternative methods. In addition, there were significant differences between female and male physicians in their beliefs about how to improve health care, regardless of whether they resided in East or West Berlin. Conclusions: The results of this study may serve as a basis for reflection on how different social circumstances and health care policies can influence the improvement of maternal and child health care.     

A sequential chart for the audit-based evaluation of screening mammogram interpretation

RATIONALE AND OBJECTIVES: Auditing has received much attention recently as a method for radiologists to use to evaluate their interpretation of screening mammograms. U.S. Food and Drug Administration regulations require that some sort of audit be in place before a mammography screening facility can receive accreditation. Auditing presents a unique opportunity to monitor accuracy continually and identify problems early. Audit data present unique challenges, however, and appropriate methods must be used to control the risk of errors. MATERIALS AND METHODS: This article introduces a simple method for the task of deciding if a radiologist yields an acceptable positive predictive value based on audit. The method is based on "sequential" decision-making techniques that have found wide application in quality control problems. These techniques are developed for diagnostic radiology and embodied in an easy-to-use decision-making chart. RESULTS: Several examples, based on audit data from actual mammography facilities, provide insights into the use of these charts and the influence of (a) the selection of standards, (b) the selection of error risks, and (c) radiologist variability. The examples also serve to demonstrate another important property of this method--that is, it specifies the minimum amount of data that has to be collected before any decision can reliably be made. CONCLUSION: The chart presented in this article provides a method by which audit data can be used objectively to evaluate the accuracy of screening mammogram interpretation. The method controls the risk of either falsely accepting an unqualified radiologist or falsely rejecting a qualified radiologist. It should be a useful tool to radiologists who must evaluate their own practices.     

Recombinant Human Erythropoietin and Hemoglobin Concentration at Operation and during the Postoperative Period: Reduced Need for Blood Transfusions in Patients Undergoing Colorectal Surgery—Prospective Double-blind Placebo-controlled Study

p < 0.05). On postoperative days 3 and 7 the values were 7.2 (5.3–8.2) and 7.5 (5.4–9.4) mmol/L, respectively, in the erythropoietin group compared to 6.7 (5.2–7.8) and 6.9 (5.1–8.6) mmol/L in the placebo group ( p < 0.01). At discharge the hemoglobin concentration was 7.8 (5.9–8.8) mmol/L in the erythropoietin group and 7.2 (5.4–8.6) mmol/L in the placebo group ( p < 0.002). The blood loss during operation was similar in the two groups. In the erythropoietin group the median value was 280 ml (range 25–2000 ml), with the lower and upper quartiles 150 and 500 ml, respectively. In the placebo group the blood loss was median 300 ml (range 50–1800 ml), with the lower and upper quartiles 200 and 750 ml, respectively. The number of blood transfusions given was significantly lower in the erythropoietin group, with a mean of 0.3 (range 0–6) units compared to 1.6 (0–9) units in the control group ( p < 0.05). In conclusion, the hemoglobin concentration at the time of surgery and during the week following surgery was significantly higher in the group of patients receiving r-HuEPO perioperatively compared to the placebo group together with a significant lower use of blood transfusions in the r-HuEPO group. However, the clinical implications of these findings has yet to be proven.RID=" ID=" <E5>Correspondence to:</E5> N. Qvist, M.D., D.Sci.     

Pharmacological activation of the ryanodine receptor in Jurkat T-lymphocytes

1 Recently, we provided evidence for cyclic adenosine 5'-diphosphate-ribose, cADP-ribose, as a second messenger in Jurkat T-lymphocytes upon stimulation of the T-cell receptor/CD3- complex (Guse et al., 1999). cADP-ribose mobilizes Ca2+ from an intracellular Ca2+ store which is sensitive to caffeine and gated by the ryanodine receptor/Ca2+ release channel. In the present study we investigated the ability of the trypanocidal drug, suramin, to activate the ryanodine receptor of T-cells. Since suramin cannot permeate the plasma membrane, it was necessary to microinject the drug into Fura-2 loaded T-lymphocytes. 2 In a dose dependent manner suramin increased the intracellular Ca2+ concentration. The dose-response curve is very steep and calculates for an EC50 of 7. 6+/-2.9 mM suramin in the injection pipette. 3 Co-injection of the selective ryanodine receptor inhibitor ruthenium red completely abolished the suramin induced Ca2+ transient. This finding allows for the conclusion that the IP3-receptor sensitive Ca2+ pool is not the primary target of the suramin induced Ca2+ transient. 4 Furthermore, Ins(1,4,6)PS3, an antagonist of the InsP3-receptor could not suppress the suramin-induced Ca2+ signal. The suramin induced Ca2+ transients declined very slowly; however, in the presence of Ins(1,4,6)PS3 this decay was accelerated. In addition, suramin did not interact with the cADP-ribose binding site of the ryanodine receptor of T-cells. 5 In conclusion, suramin is found to be an agonist for the T-cell ryanodine receptor as previously found for the cardiac and skeletal muscle isoform. Therefore, suramin can be designated a universal ryanodine receptor agonist.     

Hormonal and immunological status of children with thymus hyperplasia

The state of the adrenocortical system, cellular and humoral immunity was studied in 152 infants, suffering from thymomegaly, associated with virus-bacterial pneumonia. The results obtained allow one of to consider the hormonal and immunological state of the patients with thymomegaly to be inhibited and the adrenocortical hypofunction to be secondary. Therefore, the infants with thymomegaly should be separated into a special "risk" group, according to their immunodeficient states, respiratory allergies, acute and chronic adrenocortical deficiency.     

Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo.

For the first time the human intestinal effective permeability, estimated from the luminal disappearance and intestinal metabolism of phytochemicals, sulforaphane and quercetin-3,4'-glucoside, as well as the simultaneous changes in gene expression in vivo in enterocytes, has been studied in the human jejunum in vivo (Loc-I-Gut). Both compounds as components of an onion and broccoli extract could readily permeate the enterocytes in the perfused jejunal segment. At the physiologically relevant, dietary concentration tested, the average effective jejunal permeability (Peff) and percentage absorbed (+/- S.D.) were 18.7 +/- 12.6 x 10-4 cm/s and 74 +/- 29% for sulforaphane and 8.9 +/- 7.1 x 10-4 cm/s and 60 +/- 31% for quercetin-3,4'-diglucoside, respectively. Furthermore, a proportion of each compound was conjugated and excreted back into the lumen as sulforaphane-glutathione and quercetin-3'-glucuronide. The capacity of the isolated segment to deconjugate quercetin from quercetin-3,4'-diglucoside during the perfusion was much higher than the beta-glucosidase activity of the preperfusion jejunal contents, indicating that the majority (79-100%) of the beta-glucosidase capacity derives from the enterocytes in situ. Simultaneously, we determined short-term changes in gene expression in exfoliated enterocytes, which showed 2.0 +/- 0.4-fold induction of glutathione transferase A1 (GSTA1) mRNA (p < 0.002) and 2.4 +/- 1.2-fold induction of UDP-glucuronosyl transferase 1A1 (UGT1A1) mRNA (p < 0.02). The changes in gene expression were also seen in differentiated Caco-2 cells, where sulforaphane was responsible for induction of GSTA1 and quercetin for induction of UGT1A1. These results show that food components have the potential to modify drug metabolism in the human enterocyte in vivo very rapidly.     

Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer.

PURPOSE: To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study. PATIENTS AND METHODS: Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR). RESULTS: One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P =.71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation. CONCLUSION: Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.     

Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.