Characterization of endopeptidase 3.4.24.11 ("enkephalinase") activity in human plasma and cerebrospinal fluid

The presence of the neutral metallo-endopeptidase 3.4.24.11 ("enkephalinase") activity was investigated by fluorimetric assay in human body fluids. Although the enzyme was previously known to occur exclusively in membrane bound form in the human or animal central nervous system, its activity was detected in human cerebrospinal fluid (CSF), plasma and amniotic fluid. Although the endopeptidase 3.4.24.11 activity found in human body fluids has properties closely related to the membrane bound enzyme such as affinity constant for the inhibitors, optimal pH and Km for the substrate, the Vmax values were in CSF, plasma and amniotic fluid, respectively, 2 x 10(3), 10(2), 10 lower than mouse brain homogenate.     

Phase II evaluation of esorubicin (4′ deoxydoxorubicin) in pancreatic adenocarcinoma: A Southwest Oncology Group study

Summary Esorubicin (4 deoxydoxorubicin) is a new analogue of the anthracycline, doxorubicin. This compound lacks the hydroxyl group at 4 position on the amino sugar of the anthracycline. Phase II study was designed to determine the clinical response rate and to define the qualitative and quantitative toxicities of esorubicin in patients with adenocarcinoma of the pancreas. Fifty-eight patients with inoperable adenocarcinoma of the pancreas were entered on the study, 47 were evaluable for response, and 57 were evaluable for toxicity. The dose of esorubicin was 30 mg/m² for good risk patients and 25 mg/m² for poor risk patients every 21 days and administered IV push through a side arm of a running IV. Diphenhydramine, 50 mg is administered IM prior to the administration of the drug to block local venous reaction. Subsequent doses of esorubicin were modified according to granulocyte and platelet nadirs and the drug was not administered until recovery of platelets (> 100,000/ul) and wbc (> 3000/ul). Three partial responses, 20 stable, and 31 with increased disease were observed. Forty-seven had severe granulocytopenia (< 250), and two patients had severe thrombocytopenia (< 25,000). One patient experienced a decrease in left ventricular ejection fraction with a total dose of 180 mg/m². The dose of esorubicin in this study demonstrated that the drug has minimal activity in adenocarcinoma of the pancreas but the toxicity is tolerable. Search should continue for single agents with activity in this disease.     

Impairment of neocortical metabolism predicts progression in Alzheimer's disease

Progression rates of Alzheimer's disease (AD) vary considerably, and they are particularly difficult to predict in patients with mild cognitive impairment. We performed a prospective multicenter cohort study in 186 patients with possible or probable AD, mostly with presenile onset. In a cross-sectional analysis at entry, impairment of glucose metabolism in temporoparietal or frontal association areas measured with positron emission tomography was significantly associated with dementia severity, clinical classification as possible versus probable AD, presence of multiple cognitive deficits and history of progression. A prospective longitudinal analysis showed a significant association between initial metabolic impairment and subsequent clinical deterioration. In patients with mild cognitive deficits at entry, the risk of deterioration was up to 4.7 times higher if the metabolism was severely impaired than with mild or absent metabolic impairment. Copyrightz1999S.KargerAG, Basel     

The xenotransplantation of goat and human hematopoietic cells to sheep fetuses

Hematopoietic xenografts were carried out in three experiments using goat fetal liver (44-48 days, experiments I and II) or purified human CD 34+ cells (experiment III) as the donor cells. Recipients were sheep fetuses at 41-47 days of gestation. Goat fetal liver cells were either injected without any pretreatment or stimulated by preincubation in a culturing in goat phytohemagglutinin-stimulated lymphocyte supernatant. Human CD 34+ myeloid progenitor cells were purified from bone marrow by minimacs immunomagnetic purification and cultured in medium supplemented with stem cell factor, IL3, and IL6. Goat-sheep chimerism was assessed by flow cytometry analysis (FCA) of peripheral blood and bone marrow cells using a mouse anti-goat CD 45 monoclonal antibody and by karyotype analysis of peripheral blood from goat/sheep chimeras. Human cell engraftment was assessed by polymerase chain reaction amplification of the human DAX1 gene in blood and bone marrow DNA from sheep which had received human cells. In the three experiments, a mean of 76% (26 of 34) of injected fetuses were born alive without any clinical evidence of graft-versus-host disease. Three lambs were found to be goat/sheep chimeric after flow cytometry analysis (peripheral blood and bone marrow) and karyotype (peripheral blood) analysis. Both tissues continued to express goat cells at 6 or 12 months (last assessment) depending on the experiment. No human chimerism was detected using polymerase chain reaction amplification in peripheral blood and bone marrow of any of the six sheep grafted with human cells. These data and those also obtained on other species (human, pig/sheep) show that it is possible to carry out hematopoietic xenografts using the sheep fetus as recipient provided both donor and recipient fetal cells are processed during the period of tolerance to foreign antigens.     

An international outbreak of Vero cytotoxin-producing Escherichia coli O157 infection amongst tourists; a challenge for the European infectious disease surveillance network

In March 1997, an outbreak of Vero cytotoxin-producing Escherichia coli O157 (VTEC) infection occurred amongst holidaymakers returning from Fuerteventura, Canary Islands. For the investigation, a confirmed case was an individual staying in Fuerteventura during March 1997, with either E. coli O157 VTEC isolated in stool, HUS or serological evidence of recent infection; a probable case was an individual with bloody diarrhoea without laboratory confirmation. Local and Europe-wide active case finding was undertaken through national centres, Salm-Net and the European Programme of Intervention Epidemiology, followed by a case-control study. Fourteen confirmed and one probable case were identified from England (7), Finland (5), Wales (1), Sweden (1) and Denmark (1) staying in four hotels. Three of the four hotels were supplied with water from a private well which appeared to be the probable vehicle of transmission. The case-control study showed illness was associated with consumption of raw vegetables (OR 8.4, 95% CI 1-5-48.2) which may have been washed in well water. This investigation shows the importance of international collaboration in the detection and investigation of clusters of enteric infection.     

The characterization of biological features in dedifferentiated liposarcomas by means of principal components and discriminant analyses of 25 computer-generated variables from Feulgen-stained nuclei and histological slides

Several groups of lipomatous tumors are not yet clearly characterized on the biological level. In order to attempt to classify the dedifferentiated liposarcomas with respect to other types of malignant liposarcomas, 80 adipose tumors were submitted to the combination of two computer-assisted methodologies. These two methodologies consisted of i) the determination of 25 variables, and ii) the analysis of the diagnostic information contributed by these 25 variables by means of two complementary techniques, i.e. principal components and discriminant analyses. The 25 variables were computed by means of image cytometry on Feulgen-stained nuclei and histological slides, quantitatively describing distinct biological characteristics relating to morphonuclear (chromatin pattern) features (14 variables), nuclear DNA content distribution (9 variables), and tissue architecture pattern (2 variables). The 80 adipose tumors included 21 typical lipomas, 7 atypical lipomas (defined as extremity adipose tumors with a histopathological pattern of well-differentiated liposarcomas), 16 retroperitoneal and 5 non-retroperitoneal abdominal well-differentiated liposarcomas, 9 dedifferentiated liposarcomas, 8 myxoid (intermediate-grade tumor) and 14 pleomorphic (high-grade tumor) liposarcomas. The data strongly suggest that the dedifferentiated liposarcomas exhibit biological characteristics which are distinct from those of low- and high-grade liposarcomas, but similar to those of intermediate ones. The results also show that typical and atypical lipomas are two distinct biological entities. In contrast, the atypical lipomas and the well-differentiated retroperitoneal and non-retroperitoneal liposarcomas exhibited a high number of similar biological characteristics. Computer-assisted methods contribute valuable information to characterize lipomatous tumor biology.