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PubMed2000

DNA damage in human leukocytes after ischemia/reperfusion injury.

Leukocytes have been shown to play an important role in the development of tissue injury after ischemia and reperfusion (I/R). In the present study, the effects of tourniquet-ischemia on induction of DNA damage in peripheral leukocytes and on respiratory burst of neutrophils in humans were examined. The DNA damage was measured as increased migration of DNA using the single-cell gel-electrophoresis technique (comet assay). Intracellular production of reactive oxygen species by neutrophils was measured flow-cytometrically using dihydrorhodamine 123 as indicator. Postischemic, significantly increased migration of DNA was found in leukocytes of 20 patients (tourniquet-ischemia of the lower limb for 65-130 min, anterior-cruciate-ligament-reconstruction) and in 10 experiments (1 volunteer, repeated tourniquet-ischemia of the upper limb for 60 min, no operation). DNA effects were most pronounced 5-30 min after tourniquet release, and then declined over a 2 h period, but did not return to preischemic baseline values. A similar time course showed the oxidative status of unstimulated granulocytes during reperfusion. Simultaneously, opposing changes were measured in formyl peptide (f-MLP)- or phorbol ester (PMA)-stimulated granulocytes, which showed a significantly declined respiratory burst reaction after tourniquet-release indicating preactivation of neutrophils by IR. Our data suggest that IR induces genotoxic effects in human leukocytes presumably in response to oxidative stress during reperfusion.

Adult↗
PubMed2000

Acetabular revision after failed total hip arthroplasty in patients with congenital hip dislocation and dysplasia. Results after a mean of 8.6 years.

BACKGROUND: Revision of a total hip arthroplasty in a patient who has had congenital hip dysplasia or dislocation is often more difficult than a standard revision operation. The purpose of this study was to assess the efficacy and complications of use of a cementless hemispherical acetabular component for revision of an acetabular component of a failed total hip replacement in patients whose initial problem was arthritis secondary to congenital dislocation or dysplasia. The mean duration of follow-up was approximately eight years. METHODS: We reviewed a consecutive series of sixty-one hips in fifty-three patients who underwent a cementless acetabular revision with use of a hemispherical acetabular component, with or without concurrent femoral revision. Data were collected prospectively. The mean age of the patients at the time of the index operation was fifty-six years. A mean of 1.9 ipsilateral hip operations had been performed previously. Thirty-nine hips (64 percent) had a so-called high hip center prior to the index revision. With one exception, the uncemented acetabular component was fixed with screws. Fifty-one acetabular components were placed with so-called line-to-line fit, and ten were oversized by one to three millimeters. In thirty-eight hips, the femoral component was revised as well. Twenty-nine femora were reconstructed with use of a cemented device, and nine were revised with an uncemented patch-porous-coated femoral stem (a stem on which the porous coating appears in patches). RESULTS: Four patients (five hips) died prior to the five-year minimum follow-up interval. With the exception of one hip treated with resection arthroplasty because of deep infection, none of the hips in these deceased patients had been revised or had a loose component. One living patient (one hip) had a resection arthroplasty, and one additional patient (two hips) had both stable acetabular components rerevised at the time of femoral rerevision at another institution because of loosening and osteolysis. One patient refused to return for follow-up, but the components had not been revised. The remaining fifty-two hips in forty-six patients were followed for a mean of 8.6 years (range, 5.0 to 12.7 years). The mean Harris hip score was 80 points (range, 56 to 100 points) at the time of the latest follow-up. No acetabular component had been revised, although two had migrated. No other acetabular component was loose according to our radiographic criteria. Thus, the mechanical failure rate on the acetabular side was 3 percent (two of sixty-one) for the entire series and 4 percent (two of fifty-two) for the patients who had been followed for a mean of 8.6 years. On the femoral side, the mechanical failure rate was 3 percent (one of twenty-nine) for the cemented stems and six of nine for the uncemented patch-porous-coated stems. CONCLUSIONS: Of the approaches used in this difficult series of patients requiring revision, the hybrid arthroplasty (a cementless acetabular component and a cemented femoral component) yielded overall good results after an intermediate duration of follow-up.

Acetabulum↗
PubMed1989

Circular on controlling the outflow of labourers, March 1989.

In early March 1989, China's General Office of the State Council issued an urgent Circular demanding that various local governmental bodies "do a good job in strictly controlling the blind outflow of laborers." The circular pointed out that "since the Spring Festival, large numbers of laborers from Sichuan, Henan, Hubei, Shandong, Shaanxi, Jiangsu, Zhejiang, Anhui, and other provinces have concentrated in large numbers in regions such as the northwest, the northwest, and Guangdong Province, causing a huge increase in railroad passenger traffic. There has been a large pile-up of passengers on some main railroad lines and stations, and trains have been seriously overcrowded. This has put tremendous pressure on railroad transport. After arriving in the above mentioned regions, some of these laborers hang around the streets because they cannot find work, and their life is extremely difficult. The large influx of laborers into these regions has caused confusion in local social order." In order to resolve this problem satisfactorily, the circular makes the following demands: "The people's government at all levels must rapidly get under control the blind outflow of laborers and their assembly in large numbers for moving elsewhere. It is necessary to organize forces to admonish and stop those laborers who have already assembled at the railroad stations, so that they will not blindly move elsewhere. They should also be mobilized to return to their home towns."

Asia↗
PubMed2003

Polysialylated insulin: synthesis, characterization and biological activity in vivo.

Polysialic acids (PSA) (colominic acid; CA) of 22 and 39 kDa average molecular weight were oxidized with sodium periodate at carbon 7 of the nonreducing end to form an aldehyde group. The oxidized CAs (96-99% oxidation) were then reacted with the amino groups of recombinant human insulin at various CA/insulin molar ratios (25:1 to 150:1 range) for up to 48 h in the presence of sodium cyanoborohydride (reductive amination). Polysialylated insulin conjugates were precipitated (together with intact nonreacted insulin, if any) at time intervals from the reaction mixtures with ammonium sulfate, further purified by size exclusion chromatography and/or ion exchange chromatography (IEC), and the final conjugates assayed for PSA and protein. Results showed an initial rapid conjugation rate peaking at about 12 h, to form a plateau over a period of 12-48 h. Moreover, the extent of polysialylation (CA/insulin molar ratios in the conjugate) was dependent on the PSA used, the initial CA/insulin molar ratios in the reaction mixture and the time of the coupling reaction. Thus at 48 h of incubation, CA/insulin molar ratios in the conjugates were 1.60-1.74 for the 22-kDa CA and 2.37-2.45 for the 39-kDa CA. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of intact insulin and insulin reacted with non-oxidized CA for 48 h revealed well-resolved single bands which migrated similar distances in the gel. On the other hand, polysialylated (22-kDa CA) insulin yielded multiple diffused bands suggesting heterogenicity as a result of differential polysialylation. The pharmacological activity of polysialylated insulin was compared with that of intact insulin in normal female outbred T/O mice. After subcutaneous injection of intact insulin (0.3 units per mouse), blood glucose levels were reduced to nadir values at 1 h to return to normal at 3 h. In contrast, blood glucose levels in animals injected with polysialylated insulin (0.3 units or protein equivalence for polysialylated insulin), having attained nadir values also at 1 h, returned to normal levels after 6 h (39 kDa) and 9 h (22 kDa CA-insulin). It is concluded that polysialylation offers a promising strategy for the enhancement of the therapeutic value of insulin and other pharmacologically active peptides.

Animals↗
PubMed2001

Long-term follow-up of prophylactic greenfield filters in multisystem trauma patients.

PURPOSE: The efficacy of prophylactic Greenfield filter (PGF) placement in multisystem trauma patients at high risk for venous thromboembolism has been established. The objective of this study is to demonstrate the long-term safety and durability of PGFs placed in young, active trauma patients. METHODS: Starting January 1992, all trauma patients at high risk for development of venous thromboembolism were identified for placement of PGFs. These included patients with ISS > 9 and severe closed head injury, spinal injury, pelvic fracture, multiple long bone fracture, or direct iliofemoral venous injury. Four patients with PGFs placed before the study protocol in 1992 were also included. Follow-up was attempted in all patients with at least 5 years' duration since placement of PGF using physical examination, duplex ultrasound (US), and plain abdominal radiograph. RESULTS: There were 108 patients who had a PGF placement during the period of January 1992 to June 1994 that were eligible for the study. Eighteen of these 108 (17%) patients died. Twelve of them (67%) had autopsies and medical records available to determine the cause of death, none from a pulmonary embolism. The average time of death was 2.7 months after injury. The remaining 90 patients and the 4 patients with PGFs placed before 1992 were sought for follow-up, but only 36 patients could be contacted, 33 of which returned for evaluation (35%). The mean time of follow-up from the time of injury to the time of examination was 67.7 months, and the mean age at follow-up was 38.1 years. Although six patients had mild to moderate lower extremity edema on physical examination, none of them had a deep venous thrombosis by US. Radiographs obtained in 19 of the 33 patients showed no migration or breakdown of the Greenfield filters in place. CONCLUSION: Prophylactic Greenfield filters in high-risk trauma patients are safe and durable. There appears to be no significant consequence in over 5 years of follow-up.

Adult↗
PubMed1991

The relationship between feed intake and frequency of the migrating motor complex in domestic turkeys: is there a cephalic phase?

Two studies were performed in order to test for the presence of a cephalic inhibition of migrating motor complexes (MMC) in domestic turkeys. Birds were implanted with two or three strain gauge transducers on the ileum and subjected to one of two different protocols. In Study 1 recordings of ileal motility were made under three feeding conditions: fed, fasted, and with feed pans in place before the birds but covered with plexiglass. In Study 2 the birds were either fasted, fasted with feed pans returned as soon as an MMC registered in the most orad gauge, or fasted with a minor disruption in the room (to simulate feed pan return) as soon as an MMC registered in the most orad gauge. Data from trials involving plexiglass plates did not differ significantly from data from fasted birds, and both differed significantly from the data from fed birds. Likewise, no significant differences were seen among any of the three feeding categories of Study 2. The present data show that neither the anticipation of eating, nor the presence of feed in the mouth and esophagus seem to directly influence the initiation or propagation of ileal MMC contractile activity in turkeys, supporting the view that extrinsic neural pathways are not responsible for the inhibition of the MMC.

Animals↗
PubMed1995

[Changes in proliferation and differentiation of basal cells during wound healing of rabbit corneal epithelial abrasions].

Changes in the mitotic rate and epithelial keratin expression of corneal epithelial basal cells following corneal abrasion (7.0 mm in diameter) in rabbits were studied immunohistochemically using antiproliferating cell nuclear antigen (PCNA) monoclonal antibody and anti-epithelial keratin 1 (AE1). In the non-wounded control, the mitotic rate (PCNA positive cells in the basal cell layer) was approximately 4%, and only the superficial cells were stained by AE1 monoclonal antibody. One day after wounding, migrating epithelial cells at the leading edge, which reacted to AE1, showed low mitotic activity. At days 3 and 7, the mitotic rates of basal cells of regenerating epithelium were 3 times higher than that of controls. These basal cells displayed intensive staining with AE1, while the epithelium over the unwounded cornea exhibited a normal pattern limited to superficial cells. By 14 days after injury, the mitotic rate returned to normal and all epithelial cells expressed a normal AE1 staining pattern. Theses results suggest that regeneration of corneal epithelial basal cells involves changes in keratin expression, which might correlate with changes in the mitotic rate.

Animals↗
PubMed1994

Dissociation of lipid-free apolipoprotein A-I from high density lipoproteins.

Conditions under which apolipoprotein (apo) A-I dissociates from human high density lipoproteins (HDL) during incubation in vitro have been investigated. Dissociation of apoA-I was demonstrated by non-denaturing gradient gel electrophoresis followed by immunoblotting for apoA-I and by size-exclusion chromatography. It was quantitated after ultracentrifugation as the loss of apoA-I from the fraction of d < 1.25 g/ml. ApoA-I did not dissociate from HDL when they were incubated alone at 37 degrees C for up to 24 h. Nor was there dissociation of apoA-I when the HDL were incubated either with the cholesteryl ester transfer protein (CETP) in the absence of other lipoprotein fractions or with other lipoproteins in the absence of CETP. However, when mixtures of HDL and CETP were incubated for 24 h in the presence of physiological concentrations of either very low density lipoproteins (VLDL) or low density lipoproteins (LDL), there was a dissociation of up to 36% of the apoA-I from the HDL fraction that was linear with time. The dissociation of apoA-I coincided with a time-dependent reduction in HDL particle size. The percentage of apoA-I that dissociated from HDL correlated positively with the concentrations of VLDL, LDL, and CETP in the incubation but negatively with the concentration of HDL. When lecithin:cholesterol acyltransferase was added to mixtures at the completion of 24 h of incubation with CETP, the size of the HDL increased and the dissociated apoA-I returned to the fraction of d < 1.25 g/ml. analysis of the lipoprotein-deficient fraction of d > 1.25 g/ml isolated by ultracentrifugation and of the lower molecular weight fractions recovered after size-exclusion chromatography revealed that the dissociated apoA-I was not associated with significant quantities of either cholesterol, phospholipids, or other apolipoproteins. When the dissociated apoA-I was subjected to agarose gel electrophoresis, it migrated to a prebeta position comparable to that of purified, lipid-free apoA-I. This contrasted with the original HDL that exhibited alpha migration. Thus, CETP-mediated transfers of cholesteryl esters from HDL to VLDL and LDL are accompanied not only by a reduction in HDL size but also by the progressive dissociation from HDL of a pool of prebeta-migrating, essentially lipid-free apoA-I.

Apolipoprotein A-I↗
PubMed1999

Expression of IGF-1, IGF-1 receptor and TGF-beta following balloon angioplasty in atherosclerotic and normal rabbit iliac arteries: an immunocytochemical study.

Growth factors have been implicated in the pathogenesis of restenosis (myointimal hyperplasia after coronary interventions). In this study, we examined the expression of insulin-like growth factor-I (IGF-1), IGF-1 receptor, and transforming growth factor-beta (TGF-beta) in atherosclerotic and normal rabbit iliac arteries following overstretch balloon angioplasty of the iliac arteries to create a vascular lesion. Animals were sacrificed at 0, 3, 7, 15 and 42 days post angioplasty. The iliac arteries were processed for immunocytochemical localization of IGF-1, IGF-1 receptor and TGF-beta using colloidal gold and the data were quantitatively analyzed. IGF-1, IGF-1 receptor and TGF-beta immunoreactivity were all significantly increased in atherosclerotic arteries compared to control at all of the time points examined. Following balloon angioplasty, the levels of IGF-1 and IGF-1 receptor increased significantly in both control and even further in hypercholesterolemic vessels. In control vessels, the IGF-1 levels returned to preintervention levels, while in atherosclerotic vessels, the levels of IGF-1 and IGF-1 receptor remained elevated. In addition, TGF-beta levels in control vessels showed an initial rise in the first week following injury but then returned to baseline levels. In contrast, atherosclerotic vessels demonstrated a sustained expression of TGF-beta. Thus, IGF-1 and TGF-beta expression is different in normal vs. atherosclerotic vessels following vascular injury. The intensity of expression of IGF-1 and its receptor, which is not reduced at 42 days compared to 15 days following injury, support a role for IGF-1 in smooth muscle cell proliferation and migration. The sustained increase in TGF-beta could facilitate extracellular matrix (ECM) accumulation. Local vascular therapy that is directed towards modulating the effects of IGF-1 and TGF-beta could reduce restenosis.

Angioplasty, Balloon↗
PubMed1986

Heat inactivation of starch synthase in wheat endosperm tissue.

The effect of temperature on accumulation of starch was studied in grain slices of wheat (Triticum aestivum cv SUN9E), taken 15 days after anthesis. As compared with pretreatment of such slices at 25 degrees C, pretreatment at 30 or 35 degrees C reduced the subsequent conversion of sucrose to starch. In contrast to rice (Oryza sativa cv Calrose), pretreatment of wheat soluble starch synthase in vitro at 30 degrees C or higher temperatures reduced its activity. In zymograms using nondenaturing polyacrylamide gel electrophoresis followed by activity staining, the slowest migrating band represented the most temperature sensitive isozyme. Although preincubation of a soluble enzyme sample in vitro at 25 degrees C did not result in loss of starch synthase activity, it did result in a gradual shift of zymogram banding pattern toward faster migrating species. Pretreatment of isolated starch granules at 40 degrees C increased their bound starch synthase activity. Both soluble and bound enzymes in the grains of whole wheat plants lost activity when the plants were held above 30 degrees C for 30 minutes or longer. Both activities lost from the grains after a 1 hour treatment at 37 degrees C were restored in 1 to 2 days by a return to 21 degrees C. In slices, inactivation of the soluble starch synthase was increased by incubation with 2,4-dinitrophenol. It is tentatively suggested that in vivo heat inactivation of soluble starch synthase may be a direct effect of heat on the enzyme protein and that of bound enzyme an indirect effect involving metabolic factors.

Journal Article↗
PubMed1991

Changes in phosphorylation of myc oncogene and RB antioncogene protein products during growth arrest of the murine lymphoma WEHI 231 cell line.

The expression of the protein products of the c-myc oncogene and retinoblastoma susceptibility gene (RB) was investigated during either goat anti-mouse immunoglobulin (GaMIg)- or phorbol ester (TPA)-induced growth arrest of the murine B-lymphoma cell line WEHI 231. Previously we have demonstrated that c-myc mRNA levels increase within 1-2 h of treatment, return to control levels by 4 h, and decline below these values by 24 h of treatment. Here we demonstrate that the level of c-myc protein synthesis and mRNA change in parallel. The predominant c-myc protein expressed during the time course is the one initiated at the AUG codon (P2). The myc protein synthesized following 1-2 h of anti-immunoglobulin or TPA treatment migrates more slowly in a polyacrylamide gel as a result of increased phosphorylation. This hyperphosphorylation was no longer detectable by 4-6 h of treatment. Furthermore, the hyperphosphorylated myc protein appears to be more readily extractable with salt than the hypophosphorylated form. The product of the RB gene is present in multiple phosphorylation states in exponentially growing WEHI 231 cells. By 8 h of GaMIg or TPA treatment, a hypophosphorylated form begins to be detectable and significant levels were seen by 15 h. Thus post-translational control of both c-myc and RB expression occurs during the growth arrest of WEHI 231 cells. These changes in phosphorylation may play a role in mediating the cessation of proliferation of these cells.

Animals↗
PubMed1990

Heat shock causes the collapse of the intermediate filament cytoskeleton in Drosophila embryos.

Heat shock has a dramatic effect on the organization of the cytoplasm, causing the intermediate filament cytoskeleton to aggregate at the nucleus. This has previously been shown in cultured Drosophila and mammalian cells. In this paper we analyze the heat lability of the intermediate filament cytoskeleton in early Drosophila embryos by indirect immunofluorescence. At all stages of embryogenesis tested, the intermediate filament cytoskeleton, which is maternally provided, is severely disturbed by 30 min heat shock at 37 degrees C. After the nuclei have migrated to the subcortical cytoplasm, it collapses around them. Nuclei in all heat-shocked embryos are considerably enlarged and become displaced. Embryos before cellular blastoderm stage, in which heat shock protein synthesis is not inducible, are irreversibly arrested in development by heat shock. Embryos at or after cellular blastoderm, which do synthesize heat shock proteins in response to stress, are also immediately arrested in development but continue development when returned to 25 degrees C. We discuss the possibility that cytoplasmic events such as the intermediate filament cytoskeleton rearrangement may be involved in heat shock-mediated phenocopy induction.

Animals↗
PubMedDate not supplied

Gadolinium-DTPA enhanced dynamic MR imaging in the evaluation of cisplatinum nephrotoxicity.

Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) enhanced dynamic magnetic resonance (MR) imaging was used to monitor the nephrotoxic effects of cis-platinum (cis-diamminedichloroplatinum; CDDP), a chemotherapeutic agent that produces damage in the proximal convoluted tubule. Ten New Zealand white rabbits (NZWs) were divided into two groups and were evaluated at two clinically relevant doses of CDDP. Group 1 (four NZWs) received CDDP intravenously at 125 mg/m2 over 1 h. Rabbits in Group 2 (six NZWs) were infused with CDDP at 40 mg/m2 each day for 5 consecutive days. Dynamic MR images were performed in the axial plane at 1.5 T using a gradient recalled acquisition in the steady state sequence with an echo time of 11 ms, a repetition time of 20 ms, and a flip angle of 10 degrees after a bolus injection of Gd-DTPA 0.1 mmol/kg. Thirty-two sequential post Gd-DTPA images (5.12 s/image) were obtained over 2 min 45 s at a single location. All rabbits underwent baseline normal and serial post CDDP Gd-DTPA enhanced dynamic MR scans. Analysis of the alterations in the normal pattern of renal enhancement caused by CDDP was facilitated by using a stacked profile image and quantitative region of interest measurements of signal intensity. Normally, after the injection of Gd-DTPA, a dark band promptly appears in the outer cortex of the kidneys and migrates centripetally toward the papilla, reflecting the tubular concentration of Gd-DTPA. In Group 1 rabbits, nephrotoxicity due to CDDP was observed as early as 9 h after administration of the drug, with a complete disappearance of the dark band by 7 days. In Group 2 rabbits, the band disappeared gradually and reappeared 2-10 days after the completion of CDDP treatment, indicative of tubular damage and recovery with return of the concentrating ability of the kidney. These results illustrate the feasibility of using Gd-DTPA dynamic MR as a sensitive monitor of drug induced alterations of renal function.

Acute Kidney Injury↗
PubMed2002

A theoretical perspective using resource dependency to predict the potential migration of Medicare-eligible military beneficiaries into the Department of Defense's Managed Care System.

TRICARE for Life (TFL) became effective on October 1, 2001. On that date, approximately 1.5 million Medicare-eligible military beneficiaries (MEMB) regained health care reimbursement privileges resulting in significantly reduced individual out-of-pocket costs. TFL acts as a secondary payer to an eligible beneficiary's Medicare or other health insurance. Currently, TFL beneficiaries are allowed to remain in their current health care system. However, early discussions of Public Law 106-398 recommended that MEMB seek care at military treatment facilities. The return of MEMB to military treatment facilities may have presented a number of management challenges to leaders of the Military Health System. This article applies resource dependence theory to the issue of MEMB returning to military treatment facilities under the TFL program. Resource dependency theory and a conceptual model assist in identifying a number of challenges that may adversely affect MEMB in future years should this option ever become a reality.

Health Benefit Plans, Employee↗
PubMed1985

In vitro biosynthesis of complement protein D by U937 cells.

Preliminary studies demonstrating the secretion of antigenic D by blood monocytes/macrophages led us to study the biosynthesis of D by U937 cells, a human monocyte cell line. The kinetics of secretion of D into cell culture supernatants were followed by a solid-phase radioimmunoassay and by hemolytic assay. Daily synthesis of antigenic D was nearly linear (mean +/- 1 SD = 5.3 +/- 2.2 ng D/10(6) cells) over a 6-day period. The D produced after day 2 was hemolytically active, with a specific hemolytic activity greater than (although in the same range as) D in normal serum. Cycloheximide (10(-7) M) inhibited D synthesis, which returned to the levels found in untreated cells after removal of the inhibitor. Supernatants and lysates of cells grown in the presence of [35S]methionine were incubated with rabbit anti-D serum or FD10-1, a monoclonal anti-D antibody, bound to protein A-agarose. Autoradiograms of SDS-PAGE analysis of the precipitates demonstrated a main band of an approximate m.w. of 24,000, co-migrating with purified 125I-D. Identity of this band with D was established by blocking with excess purified D. Pulse-chase studies with the use of [35S]cysteine demonstrated a single D band both intra and extracellularly. Both forms of D had the same apparent m.w. which was approximately 3000 heavier than control 125I-D. These data demonstrate that U937 cells synthesize functionally active D, which appears to be structurally and antigenically similar to D in serum.

Amino Acids↗
PubMed1987

Acquired von Willebrand disease in patients with polycythemia rubra vera.

Platelet function and factor VIII complex were evaluated in ten patients with polycythemia rubra vera. Seven patients showed abnormal epinephrine-induced aggregation. The intracellular concentrations of adenosine diphosphate (ADP) were below normal, and the ratio of adenosine triphosphate (ATP)/ADP was greater than normal. In four of eight cases, there was a decrease in ristocetin cofactor activity and a reduction in the slowly migrating forms of vWF:Ag on crossed immunoelectrophoresis. Defect of large multimers of vWF:Ag was also observed. The ratio of vWF:Ag to ristocetin cofactor was elevated in these patients. Plasma from the patients had no effect on normal plasma except in one case, in which isolated IgG appeared to cause inactivation of ristocetin cofactor. Treatment with 1-deamino-8-arginine vasopressin caused correction of the vWF abnormalities with rapid return of ristocetin cofactor to baseline in some patients. The present study shows that the alterations of multimeric structure of vWF occur in more than 50% of patients with polycythemia rubra vera and are in some part due to the inhibitor specific for vWF.

Adenosine Diphosphate↗
PubMed1998

Chronic rejection: risk factors, regulation, and possible sites of therapeutic intervention.

Clinical chronic rejection corresponds histologically to proliferative allograft vasculopathy. This disorder reflects the cumulative trauma to the allograft regardless of its origin. As a consequence of trauma, inflammation is generated, leading to endothelial and smooth muscle cell activation, smooth muscle replication and migration, and graft arterial intimal thickening. According to the current paradigm, chronic rejection can be avoided by more intensive and selective immunosuppression and by avoiding the known predisposing factors. Retransplantation experiments in experimental animals to donor or F1-strain suggest, however, that elimination of histoincompatibility does not prevent the progression of the disorder once it has been initiated. To design additional sites of intervention after the "point-of-no-return," attention has been focused on the regulation of the synthesis of growth factors, binding of the growth factors to the receptors, and to signalling downstream of the receptor. Also, inhibition of proteolytic enzymes, necessary for the locomotion of the smooth muscle cells, is a possible target. On most occasions, however, the inhibitory effect is at the most 30 to 50% of the maximal, and only the future will show whether several of these approaches must be applied concomitantly or whether genes regulating several of these processes simultaneously can be identified and exploited.

Antibodies, Monoclonal↗