Synergistic decrease of clonal proliferation, induction of differentiation, and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid

Patients with acute promyelocytic leukemia (APL) usually relapse after all-trans retinoic acid (RA) treatment because this therapy fails to eradicate the malignant clone. Our data showed that KH 1060 and other 20-epi vitamin D3 analogs alone were potent inhibitors of clonal growth of NB4 cells, an APL cell line (ED50, approximately 5 x 10(-11) M). The combination of KH 1060 and 9-cis-RA synergistically and irreversibly enhanced this effect. Neither KH 1060 nor 9-cis-RA (10(-6) M, 3 d) were strong inducers of differentiation of NB4 cells. However, 98% of the cells underwent differentiation to a mature phenotype with features of both granulocytes and monocytes after exposure to a combination of both compounds. Apoptosis only increased after incubation of NB4 cells with 9-cis-RA alone (28%) or with a combination of 9-cis-RA plus KH1060 (32%). Immunohistochemistry showed that the bcl-2 protein decreased from nearly 100% of the wild-type NB4 cells to 2% after incubation with a combination of KH 1060 and 9-cis-RA, and the bax protein increased from 50% of wild-type NB4 cells to 92% after culture with both analogs (5 x 10(-7) M, 3 d). Western blot analysis paralleled these results. Studies of APL cells from one untreated individual paralleled our results with NB4 cells. Taken together, the data demonstrated that nearly all of the NB4 cells can be irreversibly induced to differentiate terminally when exposed to the combination of KH 1060 and 9-cis-RA.     

Participation as a complicating mechanism: the effect of clinical professional and middle manager participation on hospital performance

One way hospitals complicate themselves is by increasing the participation of clinical professionals and middle managers in making strategic decisions. Using a survey methodology this article investigates the relationships between the participation of clinical professionals (MDs and RNs) and middle managers with hospital costs, as well as the possible moderating effect of strategic complexity.     

Thrombolytic therapy in Missouri hospital emergency departments: compliance with the National Heart Attack Alert Program guidelines

Adhesive interactions between leukocytes and endothelium are required for subsequent leukocyte extravasation toward inflammatory sites. Understanding the possible kinetic expression of vascular cell adhesion molecule-1 (VCAM-1) in the middle ear cavity during an inflammatory cascade in vivo may be important for clarifying local immunological responses in otitis media. Two inflammatory models were produced in the rat and involved acute middle ear mucosal and cutaneous inflammation induced after inoculation or intradermal injection of lipopolysaccharide (LPS). After intravenous injection of both 125I-labeled anti-VCAM-1 and 131I-labeled control monoclonal antibody (mAb), the kinetic expression of VCAM-1 in the middle ear and skin was assessed by local radionuclide uptake. The biodistribution of an 125I-labeled anti-VCAM-1 mAb as a potential detector of focal inflammation was examined in normal rats. Both inflammatory lesions were characterized by early and sustained (up to 24 h) expression of VCAM-1, with maximal expression at 4 h after LPS stimulation. The kinetics of VCAM-1 expression was similar among the middle ear mucosa or skin specimens studied and different stimulation methods. A similar biodistribution and clearance of radioactivity between 125I-labeled anti-VCAM-1 mAb and 131I- or 99mTc-labeled control mAb were observed. The present result suggest that functional VCAM-1 induced by LPS is expressed in both middle ear tissue and skin lesions and may play a role in the initial stage of inflammatory response produced. Although VCAM-1 upregulation is a very early event in the inflammatory cascade, 125I-labeled anti-VCAM-1 mAb may be useful for the early detection of focal inflammation in the middle ear.     

Shifting physician prescribing to a preferred histamine-2-receptor antagonist. Effects of a multifactorial intervention in a mixed-model health maintenance organization

Three receptor tyrosine kinases of the PDGF receptor family (RTKP) that clustered within 1000 Kb of the mouse chromosome 5 constitute an interesting unit that are expressed in three distinct cell lineages essential for constructing hematopoietic tissues. Namely, the c-kit gene that is expressed in hematopoietic stem cells is flanked by pdgfr alpha and flk genes expressed respectively in stromal cells and vascular endothelial cells. In this article, we review our results on their expression in the embryonic hematopoietic tissues. We found that co-expression of Flkl and c-Kit was frequently detected either in vascular endothelial cells or hematopoietic cells in the early hematopoietic tissues. On the other hand, the three RTKPs are expressed in different cell lineages in the fetal liver. On the basis of this finding, we propose two modes of embryonic hematopoiesis; hematogenic angiopoiesis and hematopoiesis.     

Seminar planning guidelines. As I see it

Small local chapter groups can present quality cost effective regional seminars. Key components are dedication of members, teamwork, and a sense of direction. The following guidelines and information can provide a framework for planning and coordinating a seminar.     

Retail yield and fabrication times for veal as influenced by purchasing options and merchandising styles

Twenty-nine selected styles of subprimals or sections of veal were obtained from a commercial facility to assist in the development of a support program for retailers. They were fabricated into bone-in or boneless retail cuts and associated components by trained meat cutters. Each style selected (n = 6) was used to generate mean retail yields and labor requirements, which were calculated from wholesale and retail weights and processing times. Means and standard errors for veal ribs consisting of five different styles (n = 30) concluded that style #2, 7-rib 4 (10 cm) x 4 (10 cm), had the lowest percentage of total retail yield (P < .05) owing to the greatest percentage of bone. Furthermore, rib style #2 required the longest total processing time (P < .05). Rib styles #3, 7-rib chop-ready, and #5, 6-rib chop ready, yielded the greatest percentage of total retail yield and also had the shortest total processing time (P < .05). Within veal loins, style #2, 4 (10 cm) x 4 (10 cm) loin kidney fat in, had the greatest percentage fat (P < .05). Loin styles #2 and #3, 4 (10 cm) x 4 (10 cm) loin special trimmed, generated more lean and fat trimmings and bone, resulting in lower percentage of total retail yields than loin style #1, 0 (0 cm) x 1 (2.5 cm) loin special trimmed (P < .05). Results indicated that bone-in subprimals and sections required more processing time if fabricated into a boneless end point. In addition, as the number of different retail cuts increased, processing times also increased.     

Contact system in healthy term newborns: reference values in cord blood

Humoral hypercalcemia refers to the elevated blood calcium levels caused by neoplasms which release a bone resorptive substance into the circulation. Previously reported infants with malignant and benign solid tumors causing humoral hypercalcemia have presented with large abdominal masses. The case we describe, a hypercalcemic infant due to an occult parathyroid hormone-related protein-containing metanephric adenoma of the kidney, shows that radionuclide bone scanning can be a useful test to identify humoral hypercalcemia. Humoral hypercalcemia stemming from a soft tissue neoplasm should be ruled out, even in the absence of clinical signs of a tumor, if bone scans show generalized uptake in the absence of hypervitaminosis D or radiological signs of bone lesions, and serum parathyroid hormone is low.     

Inter-individual variability in Ca2+ signalling in platelets from healthy volunteers: effects of aspirin and relationship with expression of endomembrane Ca2+-ATPases

Increased Ca2+ signal generation may lead to hyperactivity of platelets and contribute to thrombotic complications. Using fura-2-loaded platelets from 51 healthy volunteers, high variability was detected in the Ca2+ responses evoked by the receptor agonists, thrombin and collagen, and the inhibitor of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA), thapsigargin (Tg). Oral intake of 500mg aspirin reduced the magnitude of the Ca2+ responses, and lowered the intra-individual coefficients of variance of the responses by 50%. However, the corresponding inter-individual variance coefficients were only a little influenced by aspirin intake, pointing to subject-dependent factors in Ca2+ handling that are unrelated to thromboxane formation. With each agonist, 6-9% of the subjects had platelets with relatively high Ca2+ responses (> mean + SD) both before and after aspirin intake. In 90% (9/10) of these cases the high responsiveness was confirmed in platelets obtained 6-12 months later. The Tg- but not thrombin-induced Ca2+ responses correlated inversely with the expression levels of SERCA PL/IM 430 (SERCA-3b) in platelets. After aspirin intake, the Ca2+ responses with collagen but not thrombin correlated inversely with SERCA-2b expression. These results suggest that, in the absence of potentiating effects of thromboxane, (i) the amount of PL/IM 430-recognizable SERCA may control the Ca2+ signal when SERCA-2b is specifically inhibited (with Tg), and (ii) the expression of SERCA-2b determine the collagen- but not the thrombin-evoked Ca2+ signal. Accordingly, limited Ca2+-pumping activity by low expression of one of the SERCA isoforms is likely to be one of the factors resulting in increased platelet activity towards collagen or thapsigargin but not thrombin.