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Intra-alveolar fibrin deposition is a cardinal feature of neonatal respiratory distress syndrome and likely contributes to short-term and long-term morbidity. Previous studies have shown that fetal distal lung epithelial cell (FDLE) surfaces express procoagulant activity when incubated with adult plasma and may therefore provide one mechanism by which fibrin is generated. However, plasma concentrations of prothrombin and thrombin inhibitors differ significantly at birth and during the first weeks of life compared with adult values. Therefore, we measured thrombin-generating capacity and inhibitor complex formation in cord and adult plasma incubated in the presence of FDLE. Although starting cord plasma concentrations of prothrombin were 43% of adult values, the amount of thrombin generated was decreased by only 21%. When cord plasma concentrations of prothrombin were selectively increased to adult values, the amount of thrombin generated surpassed adult plasma by 89%. The latter observations suggested that thrombin inhibition was impaired in cord plasma compared with adult plasma and supplementation of cord plasma with antithrombin III (ATIII) as well as prothrombin returned thrombin generation to adult levels. However, the percentage of thrombin complexed to inhibitors (59%) at the completion of the experiments was similar in cord, cord plus prothrombin, cord plus prothrombin plus ATIII, and adult plasmas. Although a higher proportion of thrombin was inhibited by alpha 2-macroglobulin (alpha 2M) in cord plasma and cord plasma plus prothrombin, this did not compensate for the decreased amount of thrombin inhibited by ATIII. When cord plasma was supplemented with ATIII as well as prothrombin, the proportions of thrombin complexed by the different inhibitors were similar to those of adult plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Female athymic nude mice bearing xenografts of OV-1063 human epithelial ovarian cancer cell line were treated with potent luteinizing hormone (LH)-releasing hormone (LH-RH) antagonist SB-75 (Cetrorelix; [Ac-D-Nal(2)1, D-Phe(4 CI)2, D-Pal(3)3, D-Cit6, D-Ala10]LH-RH in which Ac-D-Nal(2) = N-acetyl-3-(2-naphthyl)-D-alanine, D-Phe(4CI) = 4-chloro-D-phenylalanine, D-Pal(3) = 3-(3-pyridyl)-D-alanine, and D-Cit = D-Citrulline) or with the agonist [D-Trp6]LH-RH. In the first experiment, SB-75 and [D-Trp6]LH-RH were administered in the form of microcapsules releasing 60 and 25 micrograms/day, respectively. In the second study, the analogs were given by daily s.c. injections in doses of 100 micrograms/day. In both experiments, tumor growth, as measured by reduction in tumor volume, percentage change in tumor volume, tumor burden, and increase in tumor doubling time, was significantly inhibited by treatment with SB-75 but not with [D-Trp6]LH-RH. Uterine and ovarian weights were reduced and serum LH levels decreased by administration of either analog. Chronic treatment with SB-75 greatly reduced the concentration of receptors for epidermal growth factor and insulin-like growth factor I in tumor cell membranes, a phenomenon that might be related to tumor growth inhibition. It is possible that the antitumoral effects of SB-75 on OV-1063 ovarian cancers are exerted not only through the suppression of the pituitary-gonadal axis, but also directly. In view of its strong inhibitory effect on the growth of OV-1063 ovarian cancers in vivo, the potent LH-RH antagonist SB-75 might be considered for possible hormonal therapy of advanced epithelial ovarian carcinoma.

This study deals with the pattern of estrogen receptors in 52 cases of invasive breast carcinoma by comparing the ligand-binding assays with dextran-coated charcoal (DCC) to an immunoperoxidase assay (IPE) technique in paraffin-embedded material from the same tumor. A modification of the IPE by adding cobalt chloride in the final reaction and counter-staining with eosin instead of hematoxylin was introduced. A significantly high correlation was found between the two compared methods (80.8% positivity by the DCC method and 80% by the IPE method). The correlation was very significant in cases where the immunohistochemical grading was higher than 4 (according to our semi-quantitative evaluation scale of 0-8), and for these cases we suggest the IPE method as highly specific and precise.

Esophageal cancer is an important problem in the United States. It results in more deaths (over 10,000 annually) than rectal cancer. Furthermore, the incidence of esophageal adenocarcinoma is increasing at a rate faster than that of nearly any other cancer and the reasons for the increase are not well understood. A variety of tumor-suppressor genes (including p53, APC, DCC and Rb) and proto-oncogenes (including prad1, EGFR, c-erb-2 and TGF alpha) may be involved in the development and progression of esophageal cancer. Clinical prognostic factors include stage, Karnofsky performance status, sex, age, anatomic location of the tumor, and degree of weight loss. A new staging system based on depth of wall penetration and lymph node involvement correlates well with prognosis for patients undergoing esophagectomy. Newer staging procedures including endoscopic ultrasound as well as the use of minimally invasive surgery, such as thoracoscopy and laparoscopy, may allow accurate staging without esophagectomy. Surgical resection provides excellent palliation; however, the chance for cure with esophagectomy alone is only 10% to 20%. Adjuvant treatment with pre- or postesophagectomy radiation may improve local-regional control but does not improve survival. Nor has preoperative chemotherapy been shown to improve survival; however, it remains an active area of investigation. Multimodality therapy, namely, chemotherapy and radiation (chemoradiation), given concurrently prior to surgical resection shows promise, with one study indicating a 5-year survival of 34%. A complete pathologic response to chemoradiation correlates with improved survival. Chemoradiation has been shown to be superior to radiation as primary management of esophageal cancer. There has been no successfully completed randomized trial of surgery versus definitive radiation or chemoradiation. However, chemoradiation represents a reasonable alternative to esophagectomy in the primary management of squamous cell carcinoma of the esophagus and chemoradiation also appears to be effective in the treatment of patients with adenocarcinoma of the esophagus, offering significant palliation and a chance for long-term survival as well. Randomized studies of preoperative chemoradiation versus surgery or versus chemoradiation alone are needed. The treatment of advanced esophageal cancer must be directed toward palliation of symptoms. Newer endoscopic techniques, including the use of expansile metal stents, laser ablation, intraluminal high-dose rate brachytherapy, BICAP tumor probe, or photodynamic therapy, offer selected patients short-term palliation.(ABSTRACT TRUNCATED AT 400 WORDS)

The major histocompatibility complex (MHC) class I region has been shown to be associated with a variety of immune and nonimmune disorders. In an effort to initiate steps designed to identify the idiopathic hemochromatosis disease gene (HFE), we have cloned and mapped two expressed messages using probes from the HLA-H subregion that lie immediately distal to the HLA-A9 breakpoint. Although the cDNA clones identify distinct multifragment families that are dispersed throughout the MHC, the gene sequences from which the two cDNA clones derive map centromeric to the HLA-B locus and are absent from the genomes of higher nonhuman primates. This suggests that a syntenic coding segment arose within a highly polymorphic region (TNF to HLA-B interval) as the result of an insertion event following the emergence of Homo sapiens. An additional syntenic cluster exists within a peak of linkage disequilibrium with the HFE gene and may define coding sequences that underlie the defect in genetic iron overload. These data generally support the concept that the class I region is potentially gene-rich and further highlight the possibility that these new coding sequences may play a role in the development of a variety of HLA-linked diseases. The observations presented suggest that interlocus exchanges have played a structural role in the genesis of the human class I region.

In order to verify the hypothesized hormone sensibility of the laryngeal carcinoma, we evaluated the level of steroid receptors in this type of neoplasm and correlated this datum with common pathological and clinical prognostic indices. Estrogen and progesterone receptors were evaluated in 105 patients with a squamous cell carcinoma and 2 patients with a mucoepidermoid laryngeal carcinoma. Receptors for androgens and glucocorticoids were evaluated in 35 patients (all with a squamous cell carcinoma). Dosage was performed on fresh neoplastic tissue using the DCC (Dextran Coated Charcoal) method. Estrogen receptors were present in 26 cases (24.3%); progesterone receptors were present in 18 cases (16.8%); both receptors were revealed in 8 patients (7.5%). Androgen receptors were evident in 4 patients (4/35, 11.4%); glucocorticoid receptors were evident in 7 patients (7/35, 20%); both receptors were revealed in 4 (11.4%) cases. No statistical difference with regard to grading, site and extension of the cancer, extralaryngeal tissue involvement or node metastasis was noted in the groups of patients with or without steroid receptors.

<h4>Background</h4>Coronary thrombolysis is an established initial approach in the treatment of acute transmural myocardial infarction. However, conjunctive anticoagulation regimens are often suboptimal. Heparin is the only intravenously administered anticoagulant approved by the USA Food and Drug Administration commonly used for this purpose. Unfortunately, it exhibits potential limitations that may either predispose arteries to reocclusion or result in failure of initial recanalization. This study was designed to determine whether consumption of heparin cofactor, antithrombin-III (AT-III), compromises the efficacy of heparin in the setting of pharmacologic fibrinolysis and, if so, whether this degradation or inactivation is directly attributable to the effects of tissue-type plasminogen activator (t-PA) or plasmin in the blood stream.<h4>Methods</h4>AT-III was assayed by Western blotting and with a microlatex particle immunoassay in buffer, plasma, or in vivo after exposure to plasmin or t-PA.<h4>Results</h4>Neither t-PA (1-10 micrograms/ml) nor plasmin (2 microM) appeared directly to degrade AT-III in purified systems or in plasma. However, levels fell in some patients treated with t-PA, albeit a minority, in association with intense thrombosis, as reflected by failure of recanalization.<h4>Conclusion</h4>Our results demonstrate that AT-III is not degraded directly by t-PA or plasmin. They suggest that intense, ongoing thrombosis is responsible for consumption of AT-III in some patients and support the hypothesis that diminution of AT-III is a manifestation rather than a cause of inadequate anticoagulation.

Huntington disease (HD) is a severe autosomal dominant neurodegenerative disorder associated with a novel gene (IT15). Recently, we reported the cloning of Hdh, the murine homologue of IT15. Here, using an interspecific backcross, we have mapped both Hdh and the mouse homologue of human alpha-adducin (Add1), a membrane-associated cytoskeletal protein gene. Both of these genes map in the same position on mouse chromosome 5 in a region associated with ancestral chromosomal rearrangements and show no recombination with D5H4S43, D5H4S115, and D5H4S62, the murine homologues of D4S43, D4S115, and D4S62, respectively. Further mapping studies of humans, mice, and other mammalian species should reveal the nature of the rearrangements affecting this chromosomal segment during mammalian evolution.

It has previously been shown that the hepatitis B virus X gene product, pX, transactivates homologous and heterologous transcriptional regulatory sequences of viruses and various cellular genes in vitro. However, there is no evidence about the reproducibility and the relevance of this phenomenon in vivo. In this study we crossbred transgenic mice expressing the X gene under the control of the human antithrombin III (ATIII) gene regulatory sequences with transgenics carrying either the chloramphenicol acetyl-transferase or the LacZ bacterial reporter genes driven by the HIV1-LTR, which is known to be activated in trans by pX. Expression of pX in the liver stimulates the HIV1-LTR driven expression of both chloramphenicol acetyl-transferase and beta-galactosidase reporter genes in double transgenic mice. No detectable increase in chloramphenicol acetyl-transferase expression was observed in tissues, such as the spleen, brain and heart, that do not express pX. Our results confirm the transactivating properties of pX in vivo for the first time and support the hypothesis that pX might indeed modify gene expression in HBV-infected hepatocytes and influence viral pathogenesis.

We describe the establishment and characterization of a novel hepatoma cell line. This cell line, designated RBHF-1, was established from a hepatocellular carcinoma of a 67-yr-old man with a history of genetic hemochromatosis. At this writing, the cells have been maintained in RPMI-1640 tissue-culture medium and fetal calf serum without any additional supplements for 30 mo. The cells form colonies on soft agar and are not tumorigenic in nude mice. The cell line is polymorphic and displays characteristics of mature hepatocytes by synthesizing albumin, alpha 2-macroglobulin, fibronectin and alpha-fetoprotein. Cytogenetic analysis shows multiple chromosomal aberrations, with a consistent deletion in the long arm and deletions or rearrangements in the short arm of chromosome 1. There is no evidence for hepatitis B or hepatitis C virus infection of the cell line. The cells contain no detectable intracellular iron after staining with Perls' stain. Unlike other hepatoma cell lines, there is no detectable binding of epidermal growth factor to RBHF-1 cells. This is the first cell line to be established from a patient with hemochromatosis, and it provides a potentially important model for the study of hepatocyte transformation in association with iron overload.

The cultured T-cell line TIL1200, established from the tumor-infiltrating lymphocytes (TILs) of a patient with advanced metastatic melanoma, recognized an antigen on most HLA-A2+ melanomas and on all HLA-A2+ cultured neonatal melanocytes in an HLA-A2 restricted manner but not on other types of tissues or cell lines tested. A cDNA encoding an antigen recognized by TIL1200 was isolated by screening an HLA-A2+ breast cancer cell line transfected with an expression cDNA library prepared from an HLA-A2+ melanoma cell line. The nucleotide and amino acid sequences of this cDNA were almost identical to the genes encoding glycoprotein gp100 or Pmel17 previously registered in the GenBank. Expression of this gene was restricted to melanoma and melanocyte cell lines and retina but was not expressed on other fresh or cultured normal tissues or other types of tumor tested. The cell line transfected with this cDNA also expressed antigen recognized by the melanoma-specific antibody HMB45 that bound to gp100. A synthetic 10-amino acid peptide derived from gp100 was recognized by TIL1200 in the context of HLA-A2.1. Since the administration of TIL1200 plus interleukin 2 resulted in regression of metastatic cancer in the autologous patient, gp100 is a possible tumor rejection antigen and may be useful for the development of immunotherapies for patients with melanoma.

Rat ovarian surface epithelial cells transformed spontaneously in vitro have been found to have homozygous deletions of the interferon alpha (IFNA) gene. This suggests that inactivation of a tumor-suppressor gene in this region may be crucial for the development of ovarian cancer. We therefore used microsatellite markers and Southern analysis to examine the homologous region in humans--the short arm of chromosome 9--for deletions in sporadic ovarian adenocarcinomas and ovarian tumor cell lines. Loss of heterozygosity occurred in 34 (37%) of 91 informative sporadic tumors, including some benign, low-malignant-potential and early-stage tumors, suggesting that it is an early event in the development of ovarian adenocarcinoma. Furthermore, homozygous deletions on 9p were found in 2 of 10 independent cell lines. Deletion mapping of the tumors and lines indicates that the candidate suppressor gene inactivated as a consequence lies between D9S171 and the IFNA locus, a region that is also deleted in several other tumors and that contains the melanoma predisposition gene, MLM.

The ability of heparin to dramatically enhance the inactivation of thrombin (IIa) by antithrombin III (ATIII) in buffer is negated through formation of a IIa-fibrin-heparin ternary complex (Hogg and Jackson, Proc Natl Acad Sci USA 86:3619, 1989; Hogg and Jackson, J Biol Chem 265:241, 1990). IIa, in this ternary complex, is protected from inactivation by ATIII. Our aim was to determine whether fibrin also compromises heparin efficacy in plasma. We found that soluble fibrin ablated the heparin-mediated prolongation of the thrombin time with half-maximal effect at 60 nmol/L fibrin. The heparin-mediated prolongation of the activated partial thromboplastin time (APTT) was also reduced by fibrin with half-maximal effects at 140 nmol/L fibrin using 0.12 U/mL heparin and 500 nmol/L fibrin using 0.25 U/mL heparin. The mechanism of inhibition of heparin activity by fibrin in plasma was determined by measuring IIa-ATIII complexes by enzyme-linked immunosorbent assay (ELISA). Fibrin was found to inhibit the heparin-catalyzed inactivation of IIa by ATIII with half-maximal effect at 97 +/- 19 nmol/L fibrin. Fibrin had no effect on the heparin-catalyzed inactivation of factor Xa by ATIII in plasma, using either standard heparin, a heparinoid preparation (Orgaran; Organon, Lane Cove, Sydney, Australia), or low-molecular weight heparin. These findings imply that fibrin is a potent modulator of heparin activity in vivo by inhibiting heparin-catalyzed IIa-ATIII complex formation through formation of ternary IIa-fibrin-heparin complexes.

DNA replication errors (RERs) in repeated nucleotide sequences due to defective mismatch repair genes have been reported in a subset of sporadic colorectal carcinomas and in the majority of tumors from patients with hereditary nonpolyposis colorectal cancer syndrome (HNPCC). We detected RER in 18 cases (13%) in a prospective series of 137 sporadic stage II and III (Dukes' B and C) colorectal carcinomas. The clinical and pathological features of the RER-positive cases differed from those without RER. The patients with RER-positive cancers tended to be somewhat younger (60 +/- 5 years, range 22-83, versus 66 +/- 1, range 27-90, P = 0.2 with unequal variances) and had a marked preponderance of tumors proximal to the splenic flexure (17/18, 94%, versus 41/119, 34%, P < 0.0001). Only two RER-positive patients (11%) had a family history of colorectal cancer. In comparison to the 41 RER-negative proximal colonic cancers, RER-positive cancers had more frequent exophytic growth (P = 0.04), large size (P = 0.03), poor differentiation (P = 0.0004), extracellular mucin production (P = 0.003) and Crohn's-like lymphoid reaction (P = 0.003), and a trend toward less frequent p53 gene product overexpression by immunohistochemistry (3/17, 18%, versus 18/41, 44%, P = 0.06). We conclude that a subset of sporadic colorectal carcinomas has unique biological features that may indicate inherited germline mutation, de novo germline mutation, or somatic mutations of the mismatch repair genes involved in HNPCC.

Thirty-six primary renal cell carcinoma samples and one metastatic lymph node DNA sample were examined for mutations of H-, K-, and N-ras and p53 genes, and genomic instability at (AC)n, (CA)n.(GT)n, and (TA)n.(GT)n repeats. No mutations were noted for H-, K-, and N-ras genes and only 2 of all the samples (5.6%) showed mutations at exon 8 of the p53 gene. Differences in unrelated microsatellites for tumor and normal DNA were detected in 9 (25.0%) of the cases examined. Somatic alterations in seven microsatellites, D3S1228, D3S643, D5S107, LPL5GT, D9S63, D17S261, and DCC, were found in 1 (2.8%), 3 (8.3%), 2 (5.7%), 5 (14.7%), 3 (8.3%), 3 (8.3%), and 3 (8.3%) cases, respectively. Five of 26 (19.2%) clear cell type and 4 of 10 (40.0%) non-clear cell type patients showed DNA instability. Two of 11 (18.2%) grade 1, 5 of 20 (25.0%) grade 2, and 2 of 5 (40.0%) grade 3 patients showed abnormal patterns. One of 2 (50.0%) stage pT1, 4 of 24 (16.7%) stage pT2, and 4 of 10 (40.0%) stage pT3 patients were shown to have microsatellite instability. In 4 of 9 alteration-positive cases (44.4%), mutations in multiple microsatellites were observed. Alterations in microsatellite instability may be more common in non-clear cell type, high-grade, and high-stage renal cell carcinoma patients.

Platelet factor 4 is a heparin-binding protein released from the alpha granules of activated platelets. This study describes the purification and identification of two forms of rat platelet factor 4, the previously characterized non-glycosylated form of 7 kDa and an additional glycosylated form of molecular mass 9 kDa. The two proteins both neutralized the antithrombin-III-dependent inhibitory activity of heparin. Although their amino acid composition was found to be the same, in the N-terminal sequence of the 9-kDa protein, the second threonine residue could not be detected and a difference of 976Da was determined by mass spectrometry. After digestion with O-glycanase and sialidase, the two proteins showed the same molecular mass. Overall consideration of these data led to identification of the higher-molecular-mass protein as a glycosylated form of rat platelet factor 4 with O-glycosylation at the second N-terminal amino acid, while the structure of the oligosaccharide core was established by mass spectrometry and sugar differentiation with lectins. The two forms of platelet factor 4 are both present in platelets and secreted after platelet activation.

Mutation of the Schizosaccharomyces pombe cdc7 gene prevents formation of the division septum and cytokinesis. We have cloned the cdc7 gene and show that it encodes a protein kinase which is essential for cell division. In the absence of cdc7 function, spore germination, DNA synthesis and mitosis are unaffected, but cells are unable to initiate formation of the division septum. Overexpression of p120cdc7 causes cell cycle arrest; cells complete mitosis and then undergo multiple rounds of septum formation without cell cleavage. This phenotype, which is similar to that resulting from inactivation of cdc16 protein, requires the kinase activity of p120cdc7. Mutations inactivating the early septation gene, cdc11, suppress the formation of multiple septa and allow cells to proliferate normally. If formation of the division septum is prevented by inactivation of either cdc14 or cdc15, p120cdc7 overproduction does not interfere with other events in the mitotic cell cycle. Septation is not induced by overexpression of p120cdc7 in G2 arrested cells, indicating that it does not bypass the normal dependency of septation upon initiation of mitosis. These findings indicate that the p120cdc7 protein kinase plays a key role in initiation of septum formation and cytokinesis in fission yeast and suggest that p120cdc7 interacts with the cdc11 protein in the control of septation.

The selection of T cell clones with mutations in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene has been used to isolate T cells reactive to myelin basic protein (MBP) in patients with multiple sclerosis (MS). These T cell clones are activated in vivo, and are not found in healthy individuals. The third complementarity determining regions (CDR3) of the T cell receptor (TCR) alpha and beta chains are the putative contact sites for peptide fragments of MBP bound in the groove of the HLA molecule. The TCR V gene usage and CDR3s of these MBP-reactive hprt-T cell clones are homologous to TCRs from other T cells relevant to MS, including T cells causing experimental allergic encephalomyelitis (EAE) and T cells found in brain lesions and in the cerebrospinal fluid (CSF) of MS patients. In vivo activated MBP-reactive T cells in MS patients may be critical in the pathogenesis of MS.

The role of the conserved hydroxy group of the Lys-Thr(Ser)-Gly [KT(S)G] triad has been studied for a class A and a class C beta-lactamase by site-directed mutagenesis. Surprisingly, the disappearance of this functional group had little impact on the penicillinase activity of both enzymes. The cephalosporinase activity was much more affected for the class A S235A (Ser235-->Ala) and the class C T316V (Thr315-->Val) mutants, but the class C T316A mutant was less impaired. Studies were extended to beta-lactams, where the carboxy group on C-3 of penicillins or C-4 of cephalosporins had been modified. The effects of the mutations were the same on these compounds as on the unmodified regular penicillins and cephalosporins. The results are compared with those obtained with a similar mutant (T299V) of the Streptomyces R61 DD-peptidase. With this enzyme the mutation also affected the interactions with penicillins and severely decreased the peptidase activity. The strict conservation of the hydroxy group on the second residue of the KT(S)G triad is thus much more easy to understand for the DD-peptidase and the penicillin-binding proteins than for beta-lactamases, especially those of class C.

We studied the effect of the glucosidase I inhibitor, N-methyl-1-deoxynojirimycin (MdN) and the mannosidase inhibitor, 1-deoxymannojirimycin (dMM) on the biosynthesis and secretion of alpha 2-plasmin inhibitor (alpha 2-PI) and antithrombin III (ATIII) in cultures of human hepatoma (Hep-G2) cells. Incubation with 1 mM MdN decreased secreted alpha 2-PI activity and antigen levels by about 40%, whereas those of ATIII were not affected. Neither inhibitor affected the messenger RNA levels as determined by Northern blotting. Pulse-chase studies using [35S]-methionine showed that MdN decreased alpha 2-PI and ATIII secretion rates. By the 18 h chase, MdN had decreased secreted alpha 2-PI to 50-60%, with little effect on ATIII. Intracellular forms of alpha 2-PI or ATIII synthesized by cells treated with 1 mM MdN were sensitive to endoglycosidase H (Endo H), whereas almost all the secreted forms were resistant, suggesting the presence of complex-type oligosaccharides. In the presence of 1 mM dMM, cells synthesized Endo H-sensitive alpha 2-PI and ATIII with similar secretion rates. These results suggest that retention of glucose on N-linked oligosaccharides not only retards the exit of alpha 2-PI and ATIII, but also changes the catabolic rate of alpha 2-PI in the endoplasmic reticulum.

In this article, recent advances in the understanding of some of the metabolic arthropathies are reviewed. Among hemoglobinopathies, sickle-cell disease is frequently the source of rheumatic syndromes, as emphasized in recent epidemiologic studies. Avascular necrosis is one of the most common features and may be disabling, leading to total joint replacement of the hip or knee. Joint effusions more rarely are observed and have been associated with subchondral bone infarctions. The clinical and radiologic presentations of the arthropathy of hemochromatosis have been extensively reviewed. Screening for the disease appears important, because it is the only way to prevent progressive worsening of organ involvement and arthropathy in particular. The rheumatic involvement in type IIa and type III hyperlipoproteinemias recently was confirmed in a case-control study. Magnetic resonance imaging appears to be useful in assessing the extent and activity of bone marrow involvement in Gaucher's disease. Replacement therapy is developing. Dialysis-associated amyloidosis remains the target of active research, which recently led to the identification of several newly recognized components, including alpha 2-macroglobulin and hyaluronan. The main component of this amyloid, beta 2-microglobulin, has been shown to be modified by advanced glycosylation products, and these changes appear to confer inflammatory properties on the molecule.

Treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid (ATRA) was associated with rapid improvement in hemostatic markers. We made serial analyses of various hemostatic parameters in seven newly diagnosed APL patients. In all patients at diagnosis, plasma fibrinogen/fibrin degradation product (fragment-E), cross-linked fibrin degradation product (D-dimer fragment), thrombin-antithrombin III complex and plasmin-alpha 2-plasmin inhibitor complex were elevated, indicating the presence of disseminated intravascular coagulation (DIC). Antithrombin III (ATIII) levels were normal in all patients except for the patient with congenital ATIII deficiency. In four patients subsequently treated with ATRA without anticoagulant therapy, these hemostatic markers returned to near-normal levels by day 7 of treatment, indicating that DIC was essentially resolved. By contrast, in three patients who received conventional chemotherapy with a continuous low-dose heparin, improvement of coagulopathy was slower than in patients treated with ATRA. These results suggest that ATRA therapy exerts the rapid improvement in abnormal hemostatic markers in APL patients without any anticoagulant therapies, by inducing differentiation of leukemic cells and, in turns no massive release of procoagulant or fibrinolytic substances from these cells.