Treatment of thrombocytosis in myeloproliferative disorders with interferon alpha-2a

In an open prospective pilot trial, we tested the effect of recombinant interferon alpha-2 a (rIFN alpha-2 a) on thrombocytosis in myeloproliferative disorders (MPD). Since October 1986, 13 patients with MPD (4 with chronic granulocytic leukemia, 4 with polycythemia vera, 3 with essential thrombocythemia and 2 with myeloid metaplasia) were treated with rIFN alpha-2 a. Platelet counts decreased in all treated patients within 2 to 10 weeks from a median value of 1,050 x 10(9)/l (range 610-1,940 x 10(9)/l) to 340 x 10(9)/l (range 230-495 x 10(9)/l). The response was dose-dependent. In 11 patients we observed a simultaneous reduction of the white blood cell count. Six patients still continue the IFN alpha-2 a therapy. In 7 treatment was discontinued, because of chronic side effects in 3, and because of noncompliance in one. In these patients, thrombocytosis recurred after discontinuation of the therapy. These results show that rIFN alpha-2 a is effective in controlling thrombocytosis in MPD. However, the long-term benefit of interferon in these disorders remains to be established.     

Milk Fever Control Principles: A Review

Three main preventive principles against milk fever were evaluated in this literature review, and the efficacy of each principle was estimated from the results of controlled investigations. Oral calcium drenching around calving apparently has a mean efficacy of 50%–60% in terms of milk fever prevention as well as prevention of milk fever relapse after intravenous treatment with calcium solutions. However, some drenches have been shown to cause lesions in the forestomacs. When using the DCAD (dietary cation-anion difference) principle, feeding rations with a negative DCAD (measured as (Na + K) – (Cl + S)) significantly reduce the milk fever incidence. Calculating the relative risk (RR) of developing milk fever from controlled experiments results in a mean RR between 0.19 and 0.35 when rations with a negative versus positive DCAD are compared. The main drawback from the DCAD principle is a palatability problem. The principle of feeding rations low in calcium is highly efficient in milk fever prevention provided the calcium intake in the dry period is kept below 20 g per day. Calculating the relative risk (RR) of developing milk fever from controlled experiments results in a very low mean RR (between 0 and 0.20) (daily calcium intake below versus above 20 g/d). The main problem in implementing the low-Ca principle is difficulties in formulating rations sufficiently low in calcium when using commonly available feeds. The use of large doses of vitamin D metabolites and analogues for milk fever prevention is controversial. Due to toxicity problems and an almost total lack of recent studies on the subject this principle is not described in detail. A few management related issues were discussed briefly, and the following conclusions were made: It is important to supply the periparturient cow with sufficient magnesium to fulfil its needs, and to prevent the dry cows from being too fat. Available information on the influence of carbohydrate intake, and on the effect of the length of the dry period and prepartum milking, is at present insufficient to include these factors in control programmes.     

Complement component C1r mediated cleavage of the heavy chain of the major histocompatibility class I antigens.

Apart from cleaving C1s, we demonstrate for the first time that: 1) at concentrations found in serum, the activated forms of the complement components C1r in addition to C1s can cleave the heavy chain of MHC class I antigens, 2) the cleavage by C1r and C1s is seemingly dependent upon a native configuration of the MHC class I antigen, since heat denaturation of the HLA antigens reduce the cleavage. The proteolytic fragments following C1 cleavage were characterized by precipitation with Con A-Sepharose, anti-MHC class I and anti-beta 2-microglobulin antibodies. The proteolysis of the alpha-chain of MHC class I was shown to take place between the alpha 2- and alpha 3- domains as estimated by the Con A-Sepharose precipitation pattern on SDS-PAGE. The alpha 1/alpha 2 fragment was still shown to interact with beta 2-microglobulin as shown by immunoprecipitation.     

An Intelligent Tool for Process Redesign: Manufacturing Supply-Chain Applications

Manufacturing enterprises face intensive competitive pressures, and many firms are forced to redesign processes just to stay even with the competition. But process redesign is an expensive, time-consuming, and labor-intensive activity, and first-generation computer-based tools are inadequate for redesign today. Alternatively, knowledge-based systems and intelligent tools have the ability to address the key intellectual activities required for effective process redesign. The research described in this article addresses an intelligent redesign tool called KOPeR. The article describes the KOPeR design and implementation and highlights its use and mechanics in the context of a manufacturing supply-chain example. It then turns to application of KOPeR as a redesign tool in the field, through an “industrial-strength” reengineering engagement, to redesign major supply-chain processes. The field results reveal insights into the use, utility, and potential of this tool in procurement, manufacturing, and beyond. The article closes with a number of promising future directions for related research.     

On lipid droplets in renal interstitial cells

Summary By ultracentrifugation of homogenates of rat renal papillae, a low density layer composed of small primary fluorescing lipid droplets was isolated. Probably the isolated lipid material originates mainly from the primary fluorescing lipid droplets of the renal interstitial cells. The isolated lipid droplets were mainly triglycerides, cholesterol esters and free longchain fatty acids. The long-chain fatty acid composition of the main components differed markedly from that of the analogous components of plasma and depot fat. The findings suggest that the complex lipids of the isolated lipid droplets are synthetized by the renal papilla and probably by the renal interstitial cells. The prostaglandin precursor arachidonic acid constitutes a significant fraction of the triglyceride long-chain fatty acids. Usually also small quantities of prostaglandins were present. Altogether the results suggest that the lipid droplets of the renal interstitial cells may function as a storage site for prostaglandin precursor.This work was supported by a grant from the Danish State Research Foundation. — The authors wish to acknowledge the support and inspiration given by E. Bojesen, M.D., Ph.D., the Institute of Experimental Medicine, Division of Endocrinology. — The authors wish to thank Dr. John E. Pike of the Upjohn Company, Kalamazoo, Michigan, for supplying the Prostaglandins used in this study.     

Risk of Infection with Leishmania spp. in the Canine Population in the Netherlands

The dog is the main reservoir of Leishmania infantum, the causative agent of visceral leishmaniasis (VL) in humans in Southern Europe. In order to identify the risk of dogs from a Leishmania non-endemic area traveling to a Leishmania -endemic area becoming infected and the risk of transmitting infection to humans in non-endemic areas an investigation was performed, in which the results of a questionnaire were combined with the results of a serologic survey.     

Cutting edge: TCR stimulation by antibody and bacterial superantigen induces Stat3 activation in human T cells.

Recent data show that TCR/CD3 stimulation induces activation of Stat5 in murine T cells. Here, we show that CD3 ligation by mAb and Staphylococcal enterotoxin (SE) induce a rapid, gradually accumulating, long-lasting tyrosine, and serine phosphorylation of Stat3 (but not Stat5) in allogen-specific human CD4+ T cell lines. In contrast, IL-2 induces a rapid and transient tyrosine and serine phosphorylation of Stat3. Compared with IL-2, CD3 ligation induces a delayed Stat3 binding to oligonucleotide probes from the ICAM-1 and IL-2R alpha promoter. CD3-mediated activation of Stat3 is almost completely inhibited by a Src kinase inhibitor (PP1), whereas IL-2-induced Stat3 activation is unaffected. In conclusion, we show that CD3 ligation by mAb and SE triggers a rapid, PP1-sensitive tyrosine and serine phosphorylation of Stat3 in human CD4+ T cells. Moreover, we provide evidence that TCR/CD3 and IL-2 induce Stat3 activation via distinct signaling pathways.     

Metabolic Characterization of Acutely Isolated Hippocampal and Cerebral Cortical Slices Using [U-<Superscript>13</Superscript>C]Glucose and [1,2-<Superscript>13</Superscript>C]Acetate as Substrates

Brain slice preparations from rats, mice and guinea pigs have served as important tools for studies of neurotransmission and metabolism. While hippocampal slices routinely have been used for electrophysiology studies, metabolic processes have mostly been studied in cerebral cortical slices. Few comparative characterization studies exist for acute hippocampal and cerebral cortical slices, hence, the aim of the current study was to characterize and compare glucose and acetate metabolism in these slice preparations in a newly established incubation design. Cerebral cortical and hippocampal slices prepared from 16 to 18-week-old mice were incubated for 15–90 min with unlabeled glucose in combination with [U-¹³C]glucose or [1,2-¹³C]acetate. Our newly developed incubation apparatus allows accurate control of temperature and is designed to avoid evaporation of the incubation medium. Subsequent to incubation, slices were extracted and extracts analyzed for ¹³C-labeling (%) and total amino acid contents (µmol/mg protein) using gas chromatography–mass spectrometry and high performance liquid chromatography, respectively. Release of lactate from the slices was quantified by analysis of the incubation media. Based on the measured ¹³C-labeling (%), total amino acid contents and relative activity of metabolic enzymes/pathways, we conclude that the slice preparations in the current incubation apparatus exhibited a high degree of metabolic integrity. Comparison of ¹³C-labeling observed with [U-¹³C]glucose in slices from cerebral cortex and hippocampus revealed no significant regional differences regarding glycolytic or total TCA cycle activities. On the contrary, results from the incubations with [1,2-¹³C]acetate suggest a higher capacity of the astrocytic TCA cycle in hippocampus compared to cerebral cortex. Finally, we propose a new approach for assessing compartmentation of metabolite pools between astrocytes and neurons using ¹³C-labeling (%) data obtained from mass spectrometry. Based on this approach we suggest that cellular metabolic compartmentation in hippocampus and cerebral cortex is very similar.