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Rhythmically active neural networks can control the modulatory input that they receive via their synaptic effects onto modulatory neurons. This synaptic control of network modulation can occur presynaptically, at the axon terminals of the modulatory neuron. For example, in the crab stomatogastric ganglion (STG), a gastric mill network neuron presynaptically inhibits transmitter release from a modulatory projection neuron called modulatory commissural neuron 1. We showed previously that the gastric mill rhythm-timed presynaptic inhibition of the STG terminals of MCN1 is pivotal for enabling MCN1 to activate this rhythm. We also showed that MCN1 excites the pyloric rhythm within the STG. Here we show that, because MCN1 stimulation conjointly excites the gastric mill and pyloric rhythms, the gastric mill rhythm-timed presynaptic inhibition of MCN1 causes a rhythmic interruption in the MCN1-mediated excitation of the pyloric rhythm. Consequently, during each protraction phase of the gastric mill rhythm, presynaptic inhibition suppresses MCN1 excitation of the pyloric rhythm, thereby weakening the pyloric rhythm. During the retraction phase, presynaptic inhibition is absent and MCN1 elicits a faster, stronger, and modified pyloric rhythm. Thus, in addition to its role in enabling a neural circuit to regulate the modulatory transmission that it receives, presynaptic inhibition is also used effectively to rhythmically control the activity level of a distinct, but behaviorally related, neural circuit.

It is not yet understood how the molecular mechanisms controlling the release of neuropeptides differ from those controlling the release of classical transmitters, mainly because there are few peptidergic synapses in which the environment at the presynaptic release sites can be manipulated. Using Aplysia californica neuron B2, which synthesizes both peptide and classical transmitters, we have established two synaptic types. When B2 is cocultured with a sensory neuron, a peptidergic synapse is formed. In contrast, when B2 is cocultured with neuron B6, a classical synapse is formed. In contrast to a common assumption, single action potentials can release both types of transmitters. The secretion of peptide and classical transmitters by B2 is inhibited by the presynaptic injection of tetanus toxin, but not by an inactive mutant. Thus a synaptobrevin-like molecule is involved in the secretion of these two types of transmitters.

<h4>Objective</h4>To determine insulin action and insulin secretory function in patients with hemochromatosis, and to find evidence for or against hypothesized pathogenetic mechanisms for the abnormal glucose metabolism associated with hemochromatosis. These mechanisms include decreased beta-cell secretion of insulin due to iron overload, insulin resistance and genetic factors.<h4>Design</h4>Prospective in vivo study.<h4>Participants</h4>Seventeen subjects with hemochromatosis, of whom 4 had cirrhosis but not diabetes mellitus, 6 had diabetes mellitus and 7 had neither; 10 controls.<h4>Interventions</h4>Insulin sensitivity and insulin secretion were determined during an intravenous glucose tolerance test. Insulin secretion was measured as the acute insulin response to glucose (AIRg). Insulin sensitivity (Si) was quantified with the minimal-model method. Of the patients with hemochromatosis, 14 agreed to undergo a second metabolic study after treatment with venous phlebotomy.<h4>Results</h4>All subjects with hereditary hemochromatosis had impaired glucose tolerance as measured by K(g) (rate of glucose disappearance). Subjects who were free of both diabetes mellitus and liver cirrhosis had a normal S1 and a decreased AIRg. In these subjects, phlebotomy treatment normalized serum ferritin levels, increased AIRg by 35% and normalized glucose tolerance (K(g)). Subjects with hemochromatosis and cirrhosis had a reduced Si and maintained a normal insulin secretion. Phlebotomy treatment did not change these parameters. Subjects with hemochromatosis and diabetes mellitus had both a reduced Si and AIRg, and these parameters were unaffected by phlebotomy treatment.<h4>Conclusions</h4>These results suggest that iron overload can impair insulin secretion and glucose tolerance early in hereditary hemochromatosis, before cirrhosis occurs. Phlebotomy treatment can reverse these defects. Impaired glucose tolerance resulting from insulin resistance in subjects with cirrhosis or diabetes mellitus is not affected by phlebotomy treatment.

Cytogenetic, allelotype, and somatic cell hybrid studies of human head and neck cancers had suggested that the long arm of chromosome 18 might carry a tumor suppressor gene locus. To directly test this hypothesis, we introduced a wild-type copy of chromosome 18 into FaDu-Hyg-R head and neck squamous carcinoma cells. Five of 10 chromosome 18 hybrid clones formed invasive carcinomas in nude mice at a significantly lower rate and after a longer latency than the parental tumor cells, whereas the five remaining clones were tumorigenic. These results indicate that tumor formation was suppressed by chromosome 18. A homozygously deleted region of 18q in FaDu-Hyg-R cells included the candidate tumor suppressor gene, Smad4/DPC4, and extended into the DCC tumor suppressor gene locus, but not Smad2/MADR2. Each of the hybrid cell lines carried a full-length donor copy of the DCC gene, independently of their capability to form tumors in vivo. In contrast, each of the hybrid clones that were either completely or partly suppressed carried an intact copy of Smad4/DPC4, whereas this gene was deleted in the two most highly tumorigenic clones. Furthermore, the presence of Smad4/DPC4 correlated with partial restoration of cellular responsiveness to transforming growth factor beta. These results provide strong evidence for tumor suppression by Smad4/DPC4.

High mobility group 1 (HMG1) protein is an abundant and conserved component of vertebrate nuclei and has been proposed to play a structural role in chromatin organization, possibly similar to that of histone H1. However, a high abundance of HMG1 had also been reported in the cytoplasm and on the surface of mammalian cells. We conclusively show that HMG1 is a nuclear protein, since several different anti-HMG1 antibodies stain the nucleoplasm of cultured cells, and epitope-tagged HMG1 is localized in the nucleus only. The protein is excluded from nucleoli and is not associated to specific nuclear structures but rather appears to be uniformly distributed. HMG1 can bind in vitro to reconstituted core nucleosomes but is not stably associated to chromatin in live cells. At metaphase, HMG1 is detached from condensed chromosomes, contrary to histone H1. During interphase, HMG1 readily diffuses out of nuclei after permeabilization of the nuclear membranes with detergents, whereas histone H1 remains associated to chromatin. These properties exclude a shared function for HMG1 and H1 in differentiated cells, in spite of their similar biochemical properties. HMG1 may be stably associated only to a very minor population of nucleosomes or may interact transiently with nucleosomes during dynamic processes of chromatin remodeling.

Hemochromatosis (HH) is an inborn error of iron metabolism, frequent among Caucasians, characterized by progressive iron loading that, if untreated, causes high morbidity and death. HLA-H, a putative HH gene, has recently been isolated. The large majority of patients so far studied are homozygous for a single mutation, which results in a cysteine-to-tyrosine substitution at amino acid 282 of the protein. A second, less frequent, variant, His63Asp, has an undefined role in the pathogenesis of the disease. Here we report that the Cys282Tyr change accounts for 69% of HH chromosomes in a series of 75 unrelated Italian patients who fulfilled well-defined criteria for HH diagnosis. Sixty-four percent of patients were Cys282Tyr homozygous, 10% were heterozygous, and 21% carried the normal allele. The same mutation was rare in normal controls. The His63Asp variant was less frequent but had a similar frequency among affected and normal chromosomes. Subjects without two copies of the Cys282Tyr change were both isolated patients and individuals from families with a 6p-linked disease. Mutation analysis of the HLA-H gene, carried out by RNA-SSCP in the latter patients, did not reveal any significant nucleotide abnormality in coding sequences and intron-exon boundaries. The absence of mutations in HLA-H gene was confirmed in three cases by direct sequencing. Major deletions or rearrangements of the gene were excluded by Southern blotting. The existence of patients with clinical and histological features of HH, but without mutations in HLA-H gene, suggests that in Italy the disease is more heterogeneous than reported in northern Europe.

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are calciotropic hormones interacting with a shared seven-transmembrane domain G protein-coupled receptor, which is located predominantly in bone and kidney. To map the interface of the bimolecular interaction between hormone and receptor, we designed and radioiodinated a bioactive, photoreactive PTH agonist, (125)I-[Nle(8,18),Lys13(epsilon-p-(3-I-Bz)Bz),L-2-Nal(23),Arg(26,2 7),Tyr34] bPTH-(1-34)NH2 ((125)I-all-R-K13). This ligand contains a photoreactive benzophenone moiety attached to the side chain of Lys13. All other lysyl residues are substituted by argynyls. The analog photocrosslinks specifically to the recombinant hPTH/PTHrP receptor stably transfected into human embryonic kidney cells (HEK-293/C-21 cells, approximately 400,000 receptors per cell), generating a diffuse approximately 87-kDa band on SDS/PAGE autoradiography. To identify the "contact domain" within the hPTH/PTHrP receptor involved in binding of (125)I-all-R-K13, the radiolabeled band containing the ligand-receptor conjugate was subjected to chemical and enzymatic cleavage. Two independent pathways of sequential digestion were used: Route A, lysyl endopeptidase C, then endo-N-glycosidase F, followed by cyanogen bromide; Route B, cyanogen bromide followed by endo-N-glycosydase F. The identified domain is in contact with position 13 in (125)I-all-R-K13 and corresponds to amino acids 173-189 of the hPTH/PTHrP receptor, located at the C-terminal region of the N-terminal extracellular domain.

beta-Methylene-BAD (8), a nonhydrolyzable analogue of benzamide adenine dinucleotide (BAD), was synthesized as potential inhibitor of human inosine monophosphate dehydrogenase (IMPDH). Treatment of 2',3'-O-isopropylideneadenosine 5'-methylenebisphosphonate (15) with DCC afforded P1,P4-bis(2',3'-O-isopropylideneadenosine) 5'-P1,P2:P3,P4-dimethylenetetrakisphosphonate (17). This compound was further converted with DCC to an active intermediate 18 which upon reaction with 3-(2',3'-O-isopropylidene-beta-D-ribofuranosyl)benzamide (19) gave, after hydrolysis and deisopropylidenation, the desired beta-methylene-BAD (8) in 95% yield. In a similar manner, treatment of 18 with 2',3'-O-isopropylidenetiazofurin (21) followed by hydrolysis and deprotection afforded beta-methylene-TAD (5) in 91% yield. Compound 8 (IC50 = 0.665 microM) was found to be a 6-8 times less potent inhibitor of IMPDH than 5 (IC50 = 0.107 microM) and was almost equally potent against IMPDH type I and type II. Although TAD and beta-methylene-TAD were bound by LADH with the same affinity, the binding affinity of 8 toward LADH (Ki = 333 microM) was found to be 50-fold lower than that of the parent pyrophosphate 7 (Ki = 6.3 microM).

In genetic hemochromatosis (GH), excess iron is deposited in parenchymal cells, whereas little iron is found in reticuloendothelial (RE) cells until the later stages of the disease. As iron absorption is inversely related to RE cells stores, a failure of RE to retain iron has been proposed as the basic defect in GH. In RE cells of GH subjects, we examined the activity of iron regulatory protein (IRP), a reliable indicator of the elusive regulatory labile iron pool, which modulates cellular iron homeostasis through control of ferritin (Ft) and transferrin receptor gene expression. RNA-bandshift assays showed a significant increase in IRP activity in monocytes from 16 patients with untreated GH compared with 28 control subjects (1.5-fold) and five patients with secondary hemochromatosis (SH) with similar iron burden (fourfold). In 17 phlebotomy-treated GH patients, IRP activity did not differ from that of control subjects. In both GH and SH monocyte-macrophages, Ft content increased by twofold and the L subunit-rich isoferritin profile was unchanged as compared with controls. IRP activity was still upregulated in vitro in monocyte-derived macrophages of GH subjects but, following manipulations of iron levels, was modulated normally. Therefore, the sustained activity of monocyte IRP found in vivo in monocytes of GH patients is not due to an inherent defect of its control, but is rather the expression of a critical abnormality of iron metabolism, eg, a paradoxical contraction of the regulatory iron pool. By preventing Ft mRNA translation, high IRP activity in monocytes may represent a molecular mechanism contributing to the inadequate Ft accumulation and insufficient RE iron storage in GH.

The identification of mutations in the SRY-related SOX9 gene in patients with campomelic dysplasia, a severe skeletal malformation syndrome, and the abundant expression of Sox9 in mouse chondroprogenitor cells and fully differentiated chondrocytes during embryonic development have suggested the hypothesis that SOX9 might play a role in chondrogenesis. Our previous experiments with the gene (Col2a1) for collagen II, an early and abundant marker of chondrocyte differentiation, identified a minimal DNA element in intron 1 which directs chondrocyte-specific expression in transgenic mice. This element is also a strong chondrocyte-specific enhancer in transient transfection experiments. We show here that Col2a1 expression is closely correlated with high levels of SOX9 RNA and protein in chondrocytes. Our experiments indicate that the minimal Col2a1 enhancer is a direct target for Sox9. Indeed, SOX9 binds to a sequence of the minimal Col2a1 enhancer that is essential for activity in chondrocytes, and SOX9 acts as a potent activator of this enhancer in cotransfection experiments in nonchondrocytic cells. Mutations in the enhancer that prevent binding of SOX9 abolish enhancer activity in chondrocytes and suppress enhancer activation by SOX9 in nonchondrocytic cells. Other SOX family members are ineffective. Expression of a truncated SOX9 protein lacking the transactivation domain but retaining DNA-binding activity interferes with enhancer activation by full-length SOX9 in fibroblasts and inhibits enhancer activity in chondrocytes. Our results strongly suggest a model whereby SOX9 is involved in the control of the cell-specific activation of COL2A1 in chondrocytes, an essential component of the differentiation program of these cells. We speculate that in campomelic dysplasia a decrease in SOX9 activity would inhibit production of collagen II, and eventually other cartilage matrix proteins, leading to major skeletal anomalies.

The DCC (Deleted in colorectal cancer) gene was first identified as a candidate for a tumour-suppressor gene on human chromosome 18q. More recently, in vitro studies in rodents have provided evidence that DCC might function as a receptor for the axonal chemoattractant netrin-1. Inactivation of the murine Dcc gene caused defects in axonal projections that are similar to those observed in netrin-1-deficient mice but did not affect growth, differentiation, morphogenesis or tumorigenesis in mouse intestine. These observations fail to support a tumour-suppressor function for Dcc, but are consistent with the hypothesis that DCC is a component of a receptor for netrin-1.

In the developing nervous system, migrating cells and axons are guided to their targets by cues in the extracellular environment. The netrins are a family of phylogenetically conserved guidance cues that can function as diffusible attractants and repellents for different classes of cells and axons. In vertebrates, insects and nematodes, members of the DCC subfamily of the immunoglobulin superfamily have been implicated as receptors that are involved in migration towards netrin sources. The mechanisms that direct migration away from netrin sources (presumed repulsions) are less well understood. In Caenorhabditis elegans, the transmembrane protein UNC-5 (ref. 14) has been implicated in these responses, as loss of unc-5 function causes migration defects and ectopic expression of unc-5 in some neurons can redirect their axons away from a netrin source. Whether UNC-5 is a netrin receptor or simply an accessory to such a receptor has not, however, been defined. We now report the identification of two vertebrate homologues of UNC-5 which, with UNC-5 and the product of the mouse rostral cerebellar malformation gene (rcm), define a new subfamily of the immunoglobulin superfamily, and whose messenger RNAs show prominent expression in various classes of differentiating neurons. We provide evidence that these two UNC-5 homologues, as well as the rcm gene product, are netrin-binding proteins, supporting the hypothesis that UNC-5 and its relatives are netrin receptors.

Two novel series of iodinated N-substituted analogs of 2beta-carbomethoxy-3beta-(4'-iodophenyl)tropane (beta-CIT) and N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropane were synthesized. They were evaluated for their inhibitory properties on dopamine (DA(T)), serotonin (5-HT(T)), and norepinephrine (NE(T)) transporters in rat brain homogenates using [3H]GBR-12935, [3H]paroxetine, and [3H]nisoxetine as specific ligands. All new N-substituted analogs of beta-CIT exhibited higher DAT selectivity over both 5-HT(T) and NE(T) than beta-CIT. Moreover compounds with the N-substituents propynyl (6), crotyl (4), 2-bromoprop-(2E)-enyl (5), and 3-iodoprop-(2E)-enyl (3d) showed similar to higher DA(T) affinities than beta-CIT (respectively 14, 15, 30, and 30 nM vs 27 nM). Compound 3d was found to be the most selective DA(T) agent of this series (5-HTT/DA(T) = 32.0 vs 0.1 for beta-CIT). The N-(3-iodoprop-(2E)-enyl) chain linked to the tropane nitrogen was therefore maintained on the tropane structure, and phenyl substitution was carried out in order to improve DA(T) affinity. K(i) values of N-(3-iodoprop-(2E)-enyl)-2beta-carbomethoxy-3beta-(3',4'-dis ubstituted phenyl)nortropanes revealed that phenyl, 4'-isopropyl, and 4'-n-propyl derivatives weakly inhibited specific binding to DA(T), whereas phenyl substitution with 4'-methyl (3c), 3',4'-dichloro (3b), and 4'-iodo (3d) yielded high-DA(T) reuptake agents with increased DA(T) selectivity compared to beta-CIT. These results demonstrate that the combination of a nitrogen and a phenyl substitution yields compounds with high affinity and selectivity for the dopamine transporter which are usable as SPECT markers for DA neurons.

Haemochromatosis is a genetic disease associated with progressive iron overload, and is common among populations of northern European origin. HLA-H is a recently reported candidate gene for this condition. Two mutations have been identified, a substitution of cysteine for tyrosine at amino acid 282 (C282Y, nucleotide 845) and of histidine for aspartate at amino acid 63 (H63D, nucleotide 187). Over 90% of UK haemochromatosis patients are homozygous for the C282Y mutation. We have examined 5956 chromosomes (2978 people) for the presence of HLA-H C282Y and H63D by PCR followed by restriction enzyme analysis. We have found world wide allele frequencies of 1.9% for C282Y and 8.1% for H63D. The highest frequencies were 10% for C282Y in 90 Irish chromosomes and 30.4% for H63D in 56 Basque chromosomes. C282Y was most frequent in northern European populations and absent from 1042 African chromosomes, 484 Asian chromosomes, and 644 Australasian chromosomes. The distribution of the C282Y mutation coincides with that of populations in which haemochromatosis has been reported and is consistent with the theory of a north European origin for the mutation. The H63D polymorphism is more widely distributed and its connection with haemochromatosis remains unclear.

As inherited germ line mutations, such as loss of BRCA1 or AT, account for less than 5% of all breast cancer, most cases involve acquired somatic perturbations. Cumulative lifetime exposure to bioavailable estradiol links most known risk factors (except radiation) for breast cancer. Based on a series of recent experimental and epidemiologic findings, we hypothesize that the multistep process of breast carcinogenesis results from exposure to endogenous or exogenous hormones, including phytoestrogens that directly or indirectly alter estrogen metabolism. Xenohormones are defined as xenobiotic materials that modify hormonal production; they can work bifunctionally, through genetic or hormonal paths, depending on the periods and extent of exposure. As for genetic paths, xenohormones can modify DNA structure or function. As for hormonal paths, two distinct mechanisms can influence the potential for aberrant cell growth: compounds can directly bind with endogenous hormone or growth factor receptors affecting cell proliferation or compounds can modify breast cell proliferation altering the formation of hormone metabolites that influence epithelial-stromal interaction and growth regulation. Beneficial xenohormones, such as indole-3-carbinol, genistein, and other bioflavonoids, may reduce aberrant breast cell proliferation, and influence the rate of DNA repair or apoptosis and thereby influence the genetic or hormonal microenvironments. Upon validation with appropriate in vitro and in vivo studies, biologic markers of the risk for breast cancer, such as hormone metabolites, total bioavailable estradiol, and free radical generators can enhance cancer detection and prevention.

Huntington's disease is caused by a mutation of the gene encoding the protein huntingtin. Features of the human disease, characterized by selective loss of neurons from the neostriatum, can be replicated in rodents by administration of excitotoxins. In both affected individuals and the rodent model, there is massive loss of striatal projection neurons with selective sparing of interneurons. Furthermore, in the human disease the earliest evidence of striatal injury is found in striosomal regions of the striatum. The mRNA encoding huntingtin is known to be expressed by neurons throughout the brain, a distribution which does not account for the selective patterns of neuronal death which are observed. Using fluorescence immunocytochemistry and confocal microscopy with an antibody to huntingtin, we have observed that in rats a subset of striatal projection neurons contains dense accumulations of huntingtin immunoreactivity (HT-ir), while most neurons in the striatum contain much smaller amounts. The intensely stained neurons are concentrated within the striatal striosomes, as defined by calbindin-D28K staining. In the matrix regions, relatively few neurons contain dense accumulations of HT-ir, and these cells always lack perikaryal staining for calbindin-D28K. Striatal interneurons, identified by the presence of immunoreactivity for choline acetyltransferase, parvalbumin, calretinin, or neuronal nitric oxide synthase, exhibit little or no HT-ir. The paucity of HT-ir in striatal interneurons, as well as the prominence of staining in a subset of striosomal neurons, mirrors the selective vulnerability of these different types of cells in early stages of human Huntington's disease and in rodent excitotoxic models of the disorder. Our observations suggest that mechanisms which modulate the accumulation of huntingtin may play a central role in the neuronal degeneration of Huntington's disease.

The formulation of analytical goals for the clinical laboratory should be based upon a wide perspective embracing multiple viewpoints. Mathematical consideration of analytical error is necessary but insufficient to address societal forces demanding increased effectiveness while also reducing costs. Appropriate goals also require the study of cognitive science, health policy research, and the measurement of subjective preferences and of predictive probability. Overall goals must focus on health outcomes that emphasize prevention or postponement of morbidity and the need for acute care. Care process variables that influence health outcomes must be identified. Process improvement through reduction in process variation can then improve health outcomes. Important process variables will be identified in the cognitive process as well as in the pre- and post-analytical phases of laboratory care. The impact of test characteristics upon the laboratory's contribution to health goals are exemplified by monitoring of oral anticoagulant, thyroxine, aminoglycoside and intensive insulin therapy plus identification of clinically occult diseases such as hypothyroidism and hemochromatosis.

One of the most interesting glycosaminoglycans (GAGs) is heparansulphate, known as the physiological activator of antithrombin III and involved in the maintenance of the antithrombotic potential of uninjured endothelium. The aim of our study was to evaluate the tolerability and effectiveness of heparansulphate with respect to sulodexide, another GAG suitable for the treatment of venous diseases. The study was performed in a open-label, controlled, with parallel and randomized groups, design. Thirty patients (aged 32-72 years) suffering from superficial thrombophlebitis were treated for two weeks with heparansulphate 100 mg t.i.d. or sulodexide 250 LSU b.i.d., both given orally. Some coagulative and fibrinolytic parameters (PT; aPTT; fibrinogen; euglobulin lysis time; t-PA; PAI-1; ATIII; alpha 2-antiplasmin; D-Dimer and platelets count) were assayed at the beginning and at the end of the study. Moreover signs and symptoms of disease (skin trophism; local pain; itch and oedema) were assessed. Heparansulphate and sulodexide were able to reduce signs and symptoms with similar degree and to significantly modify t-PA, alpha 2-antiplasmin and ATIII levels without any difference between treatments. Our issues show that heparansulphate can be useful in superficial thrombophlebitis management.

CD44 is a family of transmembrane glycoproteins that act mainly as a receptor for hyaluronan. It can also bind some other extracellular matrix ligands (chondroitin sulphate, heparan sulphate, fibronectin, serglycin, osteopontin) with lower affinity. CD44 is encoded by a single gene containing 20 exons, 10 of which (v1-v10) are variant exons inserted by alternative splicing. The standard, ubiquitously expressed isoform of CD44, does not contain sequences encoded by these variant exons. Numerous variant isoforms of CD44 containing different combinations of exons v1-v10 inserted into the extracellular domain can be expressed in proliferating epithelial cells and activated lymphocytes. CD44 plays a significant role in lymphocyte homing. Both alternative splicing and glycosylation influence receptor function of the molecule, usually reducing its affinity to hyaluronan. The cytoplasmic domain of CD44 communicates with the cytoskeleton via ankyrin and proteins belonging to the ezrin-moesin-radixin family. Relatively little is known about the intracellular events following interactions of CD44 with its ligands. Some variant isoforms, especially those containing sequences encoded by v6-v10, are overexpressed in both human and animal neoplasms. In a rat pancreatic adenocarcinoma model one of the variant CD44 isoforms was proved to be determinant in the metastatic process. For some human neoplasms (carcinomas of the digestive tract, non-Hodgkin's lymphomas, thyroid carcinomas, and others) correlations have been made between the particular pattern of CD44 variants produced by neoplastic cells and clinicopathological parameters of tumours, such as grade, stage, presence of metastases, and survival. In vitro studies indicate that modifications of CD44 expression result in different ligand recognition and influence cell motility, invasive properties, and metastatic potential of experimental tumours. Investigation of CD44 neoexpression can be useful both in early cancer diagnosis and in predicting tumour behaviour. It can also contribute to better understanding of molecular mechanisms leading to neoplastic transformation.

We examined thrombophilic mechanisms and outcome in 54 patients with deep-vein thrombosis (DVT), who were otherwise apparently healthy and aged < or = 50 years. Patients were followed up 6 years (median) after a confirmed first DVT between 1987-1992 with no known predisposing illnesses. Patients were traced through the hospital registry and compared with 25 matched controls. Tested thrombophilic mechanisms were either genetic (activated protein C [APC] resistance; anti-thrombin III deficiency [ATIII]; protein C or protein S deficiency [PC, PS]) or acquired (lupus anti-coagulant [LAC]/anti-cardiolipin antibodies [ACA]; subsequent diagnosis of cancer). Twenty-nine DVT patients attended for full studies. The remaining 25 were interviewed by phone and none had a reported neoplastic disease, confirmed by their hospital records and the National Cancer Registry. These patients' demographics, risk factors and subsequent course were similar in all respects to the studied group. In the control group, APC resistance was the only coagulopathy found (1/25, 4%), and it was also the most common abnormality among DVT patients (8/29, 28%) (p = 0.009). Three DVT patients had LAC/ACA (10%) and one each, ATIII, PC and PS deficiencies (3.3% each). No malignancy was encountered during a follow-up of 7.9 +/- 5.7 years. Circumstantial risk factors were found in 52% of the patients, 21% had a family history of DVT, and 41% had recurrent DVT. These characteristics were not significantly different when DVT patients with and without coagulopathy were compared.