Center of excellence for placenta accreta.

Placenta accreta spectrum is one of the most morbid conditions obstetricians will encounter. The incidence has dramatically increased in the last 20 years. The major contributing factor to this is believed to be the increase in the rate of cesarean delivery. Despite the increased incidence of placenta accreta, most obstetricians have personally managed only a small number of women with placenta accreta. The condition poses dramatic risk for massive hemorrhage and associated complication such as consumption coagulopathy, multisystem organ failure, and death. In addition, there is an increased risk for surgical complications such as injury to bladder, ureters, and bowel and the need for reoperation. Most women require blood transfusion, often in large quantities, and many require admission to an intensive care unit. As a result of indicated, often emergent preterm delivery, many babies require admission to a neonatal care intensive care unit. Outcomes are improved when delivery is accomplished in centers with multidisciplinary expertise and experience in the care of placenta accreta. Such expertise may include maternal-fetal medicine, gynecologic surgery, gynecologic oncology, vascular, trauma and urologic surgery, transfusion medicine, intensivists, neonatologists, interventional radiologists, anesthesiologists, specialized nursing staff, and ancillary personnel. This article highlights the desired features for a center of excellence in placenta accreta, and which patients should be referred for evaluation and/or delivery in such centers.

RNA/DNA co-analysis from human menstrual blood and vaginal secretion stains: results of a fourth and fifth collaborative EDNAP exercise.

The European DNA Profiling Group (EDNAP) organized a fourth and fifth collaborative exercise on RNA/DNA co-analysis for body fluid identification and STR profiling. The task was to identify dried menstrual blood and vaginal secretion stains using specific RNA biomarkers, and additionally test 3 housekeeping genes for their suitability as reference genes. Six menstrual blood and six vaginal secretion stains, two dilution series (1/4-1/64 pieces of a menstrual blood/vaginal swab) and, optionally, bona fide or mock casework samples of human or non-human origin were analyzed by 24 participating laboratories, using RNA extraction or RNA/DNA co-extraction methods. Two novel menstrual blood mRNA multiplexes were used: MMP triplex (MMP7, MMP10, MMP11) and MB triplex (MSX1, LEFTY2, SFRP4) in conjunction with a housekeeping gene triplex (B2M, UBC, UCE). Two novel mRNA multiplexes and a HBD1 singleplex were used for the identification of vaginal secretion: Vag triplex (MYOZ1, CYP2B7P1 and MUC4) and a Lactobacillus-specific Lacto triplex (Ljen, Lcris, Lgas). The laboratories used different chemistries and instrumentation and all were able to successfully isolate and detect mRNA in dried stains. The simultaneous extraction of RNA and DNA allowed for positive identification of the tissue/fluid source of origin by mRNA profiling as well as a simultaneous identification of the body fluid donor by STR profiling, also from old and compromised casework samples. The results of this and the previous collaborative RNA exercises support RNA profiling as a reliable body fluid identification method that can easily be combined with current STR typing technology.

Changes in CSF acetyl- and butyrylcholinesterase activity after long-term treatment with AChE inhibitors in Alzheimer's disease.

OBJECTIVES: To measure cerebrospinal fluid (CSF) activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in patients with Alzheimer's disease (AD) participating in randomized clinical trials from three European centers, before and after long-term treatment with different AChE inhibitors (AChEIs). MATERIALS AND METHODS: Of the 144 patients included in the study, 104 were treated with donepezil, 15 with galantamine, 16 with rivastigmine, and nine with placebo. CSF AChE and BChE activities were measured at baseline and after 1- year treatment. RESULTS: Donepezil and galantamine groups showed a significant increase in CSF AChE activity at follow-up, while no changes for BChE activity were observed; in donepezil group, a positive correlation between plasma concentration and AChE activity was documented. Conversely, in rivastigmine group, a decrease in CSF activity of both enzymes was observed. CSF AChE and BChE activities were not correlated with the clinical outcome in any group considered. CSF biomarkers did not show any change after treatment. CONCLUSIONS: AChEIs differently influence the activity of target enzymes in CSF independent of their pharmacodynamic effects.

GABA agonists and gabapentin for spastic hypertonia.

Spasticity is a result of an imbalance between the afferent excitatory and descending inhibitory pathways after central nervous system damage. Its pharmacologic control is believed to result from the antagonism of inhibitory mechanisms (gamma-aminobutyric acid [GABA] or glycine-mediated antagonism of excitatory mechanisms), or both. Because GABA receptor sites are widely present in the central nervous system, it is amenable to pharmacologic manipulation.

The future of biotechnology in Europe.

At the end of September '96, the Club de Bruxelles held a conference ("The Future of Biotechnologies in Europe") to discuss the present development and the future of biotechnology in Europe. The meeting was intended to serve as a forum for the preparation of the 5th EU framework ("Inventing Tomorrow"), which is currently being set up under the leadership of Edith Cresson. The aim of the conference was to underline the necessity of concentrating and reorganizing research in the field of biotechnology, thus focusing future research activities in order to secure Europe's competitiveness in the world market. The conference was attended by 350 participants from all over Europe, representing academia, industry, environmental organizations and consumer groups. Lectures were held by representatives from academic and industrial research and a variety of work groups of the European Parliament. The speakers and participants were mainly chosen to promote the dialogue between the different groups. The objectives were the creation of a common basis for further debate in the field of biotechnology and the preparation of future consent. Once again, this conference emphasized the need to inform the public as a prerequisite for the acceptance of biotechnology and its various aspects.

Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections.

A trial of the antifungal triazole fluconazole was conducted in cancer patients with presumed or proven mold infection. Groups of patients received fluconazole at four dosages (800, 1200, 1600, or 2000 mg/day). Adverse events, plasma levels, and clinical response were examined. Thirty-nine patients were enrolled. The 28 evaluable patients had presumed (13 patients) or proven (15) mold infection with Aspergillus (4) and Fusarium (3) species, Zygomycetes organisms (1), or nonspeciated mold (7). Adverse effects included elevated liver function test results (8 patients), nausea and vomiting (2), and erythema multiforme (1). Neurologic toxicity occurred in 3 patients receiving 2000 mg/day. Average steady-state peak plasma concentrations were 51.8, 74.4, and 91.8 mg/L for dosages 1200, 1600, and 2000 mg/day, respectively. Seven of 28 evaluable patients responded. Response did not appear to be related to dose. Fluconazole is well tolerated at total daily doses up to 1600 mg. The data suggest a linear plasma concentration-dose relationship. The activity of fluconazole in refractory mold infections seems to be limited.

Expression of interleukin 10 in human melanoma.

The expression of interleukin 10 (IL-10) mRNA in human malignant melanoma was investigated by reverse transcriptase polymerase chain reaction analysis. Selective expression of IL-10 mRNA in tissues of primary melanomas and melanoma metastases was found in comparison with normal skin. In addition, strong expression of IL-10 mRNA and of biologically active IL-10 was detected in 3 out of 13 melanoma cell lines. Normal melanocytes consistently expressed low levels of IL-10 mRNA but did not produce detectable IL-10 protein, nor did keratinocytes or fibroblasts. The production of biologically active IL-10 by melanoma cell lines suggests that IL-10 mRNA in melanoma lesions may derive at least in part from the tumour cells themselves. Tumour-infiltrating cells, however, could also be a source of IL-10 in melanoma tissues. The presence of IL-10 in melanoma lesions may contribute to the postulated 'paralysis' of an anti-melanoma immune response.

A sensitive and specific bioassay for the detection of human interleukin-10.

Interleukin-10 (IL-10) is a novel cytokine that is produced by T cells, macrophages, B cells and keratinocytes. It has been shown to inhibit cytokine production and proliferation by T cells when macrophages are used as accessory or antigen presenting cells. Monokine production by macrophages is effectively downregulated by IL-10 and it can be used as a growth factor by CD4, CD8 and gamma/delta positive T cells as well as mast cells and B cells. It is because of these pleiotropic immunoregulatory effects that the detection of IL-10 in the supernatants of T cells, B cells, macrophages and other cells is important for many scientific questions. Here we describe a simple and sensitive bioassay specific for human IL-10 using the IL-10 dependent growth of the mouse mast cell line D36. Our data show that this assay is not crossreactive with hIL-1 beta, hIL-2, hIL-3, hIL-4, hIL-5, hIL-6, hIL-9, hIL-12, hGM-CSF and hTNF-alpha and that it can be completely blocked by an antibody against human IL-10. The hIL-10 induced growth of the D36 cell line is dependent on the presence of mIL-4. Human IL-10 can be measured in a concentration range from approximately 10 U/ml to 0.05 U/ml. This assay is only of limited use for the measurement of IL-10 in human blood samples since it is inhibited by the presence of human serum.

Interleukin 10 transfected into Chinese hamster ovary cells prevents tumor growth and macrophage infiltration.

Expression of cytokines in tumor cells provides a sensitive modality to analyze the consequences of local cytokines in vivo on tumor infiltrating cells and tumorigenicity. We have transfected Chinese hamster ovary (CHO) cells with an interleukin 10 (IL-10) expression vector. CHO-IL10 cells although unaltered with respect to their in vitro growth lost tumorigenicity, both in nude and in SCID mice and in an IL-10 dose dependent manner. In addition, CHO-IL10 cells suppressed the growth of equal numbers of coinjected but not of contralaterally injected CHO cells. Immunohistology with anti-CR3/Mac-1 and anti-Mac-3 monoclonal antibodies revealed that CHO tumors were substantially infiltrated by macrophages. However, in CHO-IL10 tumors macrophages were virtually absent within the tumor tissue. Our results suggest that IL-10 indirectly suppresses tumor growth of certain tumors by inhibiting infiltration of macrophages which may provide tumor growth promoting activity.

Pharmacokinetics of cefepime in cystic fibrosis patients.

The purposes of this study were to determine and compare the single- and multiple-dose pharmacokinetics of cefepime in patients with and without cystic fibrosis. Twelve patients with cystic fibrosis hospitalized for treatment of acute pulmonary exacerbations were studied. In addition, pharmacokinetic data for seven of the patients with cystic fibrosis were compared with those for seven age-matched control patients. The cefepime dose was 50 mg/kg of body weight (maximum, 2 g) administered as a 30-min intravenous infusion every 8 h for a minimum of 8 days. Serial plasma and urine samples, obtained after the first and last doses, were analyzed for cefepime content by a validated high-pressure liquid chromatographic assay. By standard noncompartmental analysis, the pharmacokinetic parameters ascertained were area under the concentration in plasma-time curve, elimination half-life, total body clearance, renal clearance, and volume of distribution at steady state. In addition, the maximum concentration in plasma was recorded. Mean (+/- standard deviation) results of the first dose analysis in patients with cystic fibrosis were as follows: maximum concentration in plasma, 142.6 (+/- 26.07) micrograms/ml; area under the concentration in plasma-time curve, 265.3 (+/- 114.31) micrograms.h/ml; elimination half-life, 1.8 (+/- 0.53) h; total body clearance, 127.2 (+/- 50.94) ml/min; renal clearance, 91.1 (+/- 38.86) ml/min/kg; volume of distribution at steady state, 14.1 (+/- 4.31) liters. Analysis for the last dose in patients with cystic fibrosis did not vary appreciably from these values, nor did those from the controls. Thus, it appears that the first-dose pharmacokinetics of cefepime are predictive of those at steady state. In order to consistently exceed the MIC for Pseudomonas aeruginosa for the entire dosing interval in patients with cystic fibrosis, a higher dose and/or different dosing interval compared with those used in this study may be necessary.

Characterization of a T-cell-derived mast cell costimulatory activity (MCA) that acts synergistically with interleukin 3 and interleukin 4 on the growth of murine mast cells.

The proliferation of mucosal mast cells (MMC) depends on the presence of interleukin 3 (IL 3) and can be further enhanced by interleukin 4 (IL 4). The supernatant of a TH2 cell clone (ST2/K.9) stimulated by concanavalin A was found to contain a factor, provisionally termed mast cell costimulatory activity (MCA), that substantially enhances the proliferation of MMC promoted by a combination of IL 3 and IL 4. In comparison to other lymphokines MCA is rather resistant to tryptic digestion but is very sensitive to pH values lower than 6.0 and to organic solvents. Chromatographic fractionation of MCA revealed that activity is associated with protein(s) or glycoprotein(s) of 35 to 40 kDa. Partially purified MCA that was functionally free of other T-cell-derived lymphokines did not stimulate mast cell proliferation in the absence of a combination of IL 3 and IL 4. In addition, MCA did not affect the proliferation of mast cells when employed together with either IL 3 or IL 4 alone. Control experiments demonstrated that MCA is identical to neither the T-cell-derived lymphokines IL 2 to IL 6, IL 9, interferon gamma, tumor necrosis factor alpha or beta, or granulocyte-macrophage colony-stimulating factor (CSF), nor to IL 7, granulocyte CSF, macrophage CSF, erythropoietin, leukemia inhibitory factor, or epidermal growth factor (EGF). Finally, experiments using a panel of PPD-reactive TH1- and TH2-like cell lines revealed that MCA is preferentially produced by TH2 cells. These data, especially the relative resistance of MCA to trypsin and the high sensitivity to low pH values and organic solvents, indicate that MCA is distinct from known T-cell-derived lymphokines.(ABSTRACT TRUNCATED AT 250 WORDS)