FGF and EGF are mitogens for immortalized neural progenitors

Individual neural progenitors, derived from the external germinal layer of neonatal murine cerebellum, were previously immortalized by the retrovirus-mediated transduction of avian myc (v-myc). C17-2 is one of those clonal multipotent progenitor cell lines (Snyder et al., 1992, Cell 68: 33-51; Ryder et al., 1990, J. Neurobiol. 21:356-375). When transplanted into newborn mouse cerebellum (CB), the cells participate in normal CB development; they engraft in a cytoarchitecturally appropriate, nontumorigenic manner and differentiate into multiple CB cell types (neuronal and glial) similar to endogenous progenitors (Snyder et al., 1992, as above). They also appear to engraft and participate in the development of multiple other structures along the neural axis and at multiple other stages (Snyder et al., 1993, Soc. Neurosci. Abstr. 19). Thus conclusions regarding these immortalized progenitors may be applicable to endogenous neural progenitors in vivo. To help identify and analyze factors that promote differentiation of endogenous progenitors, we first investigated the ability to maintain C17-2 cells in a defined, serum-free medium (N2). The cells survive in vitro in N2 but undergo mitosis at a very low rate. Addition of epidermal growth factor (EGF), however, either from mouse submaxillary gland or the human recombinant protein, appreciably stimulates thymidine incorporation and cell division approximately threefold. Basic fibroblast growth factor (bFGF) is an even more potent mitogen, promoting thymidine incorporation, cell division, and a net increase in cell number equal to that in serum. Both EGF and bFGF are active at very low nanomolar concentrations, suggesting that they interact with their respective receptors rather than a homologous receptor system. The findings demonstrate that C17-2 cells can be maintained and propagated in a fully defined medium, providing the basis for analysis of other growth and differentiation factors. That EGF and particularly bFGF are mitogenic for these cells is in accord with recent observations on primary neural tissue (Reynolds and Weiss, 1992, Science 255:1707-1710; Kilpatrick and Bartlett, 1993, Neuron 10:255-265; Ray et al., 1993, Proc. Natl. Acad. Sci. USA 90:3602-3606) suggesting that bFGF and EGF responsiveness may be fundamental properties of neural progenitors.     

Localization of focal adhesion kinase in differentiating Schwann cell/neuron cultures

Previous studies have shown that Schwann cells (SCs) differentiate into myelin-forming or ensheathing cells only under conditions which allow the deposition of basal lamina and extracellular collagen [Bunge (1993) Peripheral Neuropathy, pp. 299-316]. SC adhesion to basal lamina is mediated by beta1 integrins and function blocking antibodies to beta1 integrins inhibit myelination [Fernandez-Valle et al. (1993) Development 119:867-880]. Recently, focal adhesion kinase (FAK), a cytoplasmic non-receptor tyrosine kinase, was found to mediate beta1 integrin-dependent signalling in a variety of cultured cell types adhering to ECM components such as fibronectin [reviewed in Schwartz et al. (1995) Ann. Rev. Cell Biol. 11:549-599; Ilic et al. (1997) J. Cell Sci. 110:401-407]. In the present study, we have determined more precisely the respective time courses of ECM deposition and myelination. In addition, we have studied by immunocytochemistry, immuno-gold labelling, and electron microscopy the expression and subcellular localization of FAK in nondifferentiating SCs and in SCs differentiating into myelinating cells. We show that the development of basal lamina and extracellular collagen fibrils precedes by 3 days the appearance of the first myelin sheaths. FAK was detected by immunocytochemistry or immuno-gold labelling only in SCs differentiating in the presence of ascorbic acid. Localization of FAK to the abaxonal plasma membrane was dependent upon ECM deposition. Cytochalasin D did not prevent or disrupt localization of FAK to the plasma membrane. These data support the possibility that FAK acts as an intermediate in the pathway by which basal lamina regulates SC differentiation.     

CFTR: domains, structure, and function

Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) (Collins, 1992). Over 500 naturally occurring mutations have been identified in CF gene which are located in all of the domains of the protein (Kerem et al., 1990; Mercier et al., 1993; Ghanem et al., 1994; Fanen et al., 1992; Ferec et al., 1992; Cutting et al., 1990). Early studies by several investigators characterized CFTR as a chloride channel (Anderson et al.; 1991b,c; Bear et al., 1991). The complex secondary structure of the protein suggested that CFTR might possess other functions in addition to being a chloride channel. Studies have established that the CFTR functions not only as a chloride channel but is indeed a regulator of sodium channels (Stutts et al., 1995), outwardly rectifying chloride channels (ORCC) (Gray et al., 1989; Garber et al., 1992; Egan et al., 1992; Hwang et al., 1989; Schwiebert et al., 1995) and also the transport of ATP (Schwiebert et al., 1995; Reisin et al., 1994). This mini-review deals with the studies which elucidate the functions of the various domains of CFTR, namely the transmembrane domains, TMD1 and TMD2, the two cytoplasmic nucleotide binding domains, NBD1 and NBD2, and the regulatory, R, domain.     

Characteristics of age-related behavioral changes in senescence-accelerated mouse SAMP8 and SAMP10

Senescence-Accelerated Mouse (SAM), a murine model of accelerated senescence, has been established by Takeda et al. (1981). SAM consists of senescence-accelerated-prone mouse (SAMP) and senescence-accelerated-resistant mouse (SAMR), the latter of which shows normal aging characteristics. In 1991 there were eight different substrains in the P-series, which commonly exhibited accelerated aging with a shortened life span (Takeda et al., 1991). Among the P-series, we have found that SAMP8 mice show significant impairments in a variety of learning tasks when compared with SAMR1 mice (Miyamoto et al., 1986). Further studies suggest that SAMP8 exhibits an age-related emotional disorder characterized by reduced anxiety-like behavior (Miyamoto et al., 1992). On the other hand, it has been shown that SAMP10 exhibits brain atrophy and learning impairments in an avoidance task (Shimada et al., 1992, 1993). Here, characteristics of age-related deficits in learning and memory, changes in emotional behavior, and abnormality of circadian rhythms in SAMP8 and SAMP10 mice are described. In the experiments, SAMP8/Ta (SAMP8), SAMP10/(/)Ta (SAMP10) and SAMR1TA (SAMR1) reared under specific pathogen-free conditions at Takeda Chemical Industries were used.     

A novel peptide-grafted liposomal delivery system targeted to macrophages

Insulin-like growth factor II (IGF-II) is highly expressed during hepatocarcinogenesis (P. Schirmacher et al., Cancer Res., 52: 2549-2556, 1992; B. C. Park et al., J. Hepatol., 22: 286-294, 1995). However, the mechanism of its enhanced expression is largely unknown. In this study, we show that IGF-II mRNA levels are increased within six h of exposing human hepatoma cell cultures to hypoxia, suggesting that hypoxia may be a strong stimulus for the induction of IGF-II expression in the process of hepatocarcinogenesis. This finding and the fact that hepatocellular carcinoma (HCC) is a typical hypervascular tumor (M. Mise et al., Hepatology, 23: 455-464, 1996) imply that IGF-II may play an important role in the development of neovascularization of HCC. Here we demonstrate that IGF-II substantially increases vascular endothelial growth factor (VEGF) mRNA and protein levels in a time-dependent manner in human hepatoma cells. The induction of VEGF by IGF-II was additively increased by hypoxia. Moreover, the direct angiogenic activity of IGF-II was observed in the quantitative chick chorioallantoic membrane assay (M. Nguyen et al., Microvasc. Res., 47: 31-40, 1994). These data suggest that IGF-II may be a hypoxia-inducible angiogenic factor in HCC.     

TNF-alpha bifunctionally induces proliferation in primary hepatocytes: role of cell anchorage and spreading

In the absence of a growth factor or an appropriate extracellular matrix (ECM), cells are arrested in the G0/G1 phase. In this report, we demonstrate the evidence that TNF-alpha induced DNA synthesis of primary mouse hepatocytes in vitro by activating two distinct pathways. TNF-alpha induced drastic spreading of hepatocytes on hydrophobic plastic, while the adhesion was not influenced. The effect was time and dose dependent. The cell spreading was accompanied by the phosphorylation of paxillin, indicating the stimulation of focal adhesion molecules. TNF-alpha-induced spreading of hepatocytes was not transient, and kinetic analysis and morphologic observation suggest that the effect was different from epidermal growth factor- or hepatocyte growth factor-induced transient hepatocyte spreading. TNF-alpha-induced hepatocyte spreading was blocked by cytochalasin D, Arg-Gly-Asp peptides, cycloheximide, or anti-integrin beta1 Ab. Results of competitive PCR for ECM proteins demonstrated that TNF-alpha increased the expression of laminin alpha3 and gamma1 chains in hepatocytes. These data suggested that TNF-alpha induced cell anchorage for hepatocytes by up-regulating ECM production. More importantly, TNF-alpha, but neither epidermal growth factor nor hepatocyte growth factor, induced DNA synthesis following the spreading in primary hepatocytes on hydrophobic plastic, while mere cell spreading on collagen did not induce DNA synthesis. The DNA synthesis was blocked by the inhibition of either cell spreading or DNA polymerase, demonstrating that TNF-alpha induced DNA synthesis in primary hepatocytes by activating two distinct pathways, i.e., forming the scaffold and inducing growth signals. Taken together, TNF-alpha bifunctionally regulates the proliferation of primary hepatocytes, serving as both an ECM inducer and a growth factor.     

Atractyloside-induced release of cathepsin B, a protease with caspase-processing activity

Craniosynostosis, the premature osseous obliteration of cranial vault sutures, can result from mutations in genes encoding components of growth factor signaling systems or the extracellular matrix (ECM). Little is known of the capacity of osteoprogenitor cells of the cranial sutures to divide or to synthesize ECM in situ. Osteoblasts derived from patients with prematurely fused sutures were reported to express alkaline phosphatase and osteocalcin at elevated levels, while proliferating at a rate comparable to control cells [DePollack et al., JBMR, 1996]; however, the suture osteoprogenitors, the population most likely to show proliferative abnormalities, were not present in the fused sutures used for this study. A model in which rat coronal sutures and associated bones develop normally in vitro, but in which sutures can be induced to fuse in the absence of dura mater, was used to examine cell proliferation and total protein synthesis in unfused sutures cultured in the presence of dura mater or in sutures induced to fuse in the absence of dura mater. Significantly increased cell proliferation was seen in suture cells prior to sutural obliteration, which returned to control levels as sutural fusion proceeded. Collagen synthesis in fusing sutures was elevated compared to non-fusing sutures and comparable to that seen in bone. Results indicated that in the absence of intercellular signals provided by the dura mater, suture cell proliferation increased initially, followed by increased synthesis of collagenous ECM within the suture and subsequent osseous obliteration of the suture. Thus factors originating in the dura mater affected suture cell proliferation and ECM production and were required for the maintenance of suture patency.     

Reply to comments on the child-care debate.

Responds to comments by W. B. Johnson and D. Hayes (see record 1993-41125-001), J. E. Maddux (see record 1993-41129-001), K. McCarthey et al (see record 1993-41130-001), the National Institute of Child Health and Human Development Early Child Care Network (see record 1993-41132-001), and N. Shpancer (see record 1993-41138-001) on L. B. Silverstein's (see record 1992-05293-001) original article on child care and maternal employment, noting that the comments go a long way toward expanding the child-care debate, if not transforming it. Silverstein focuses on the role of psychology in policymaking and the responsibility of government in the lives of individuals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Entropy-driven intermediate steps of oxygenation may regulate the allosteric behavior of hemoglobin

When the oxygen binding isotherms of human, bovine and fallow deer (Dama-Dama) hemoglobins are measured at different temperatures either by optical or calorimetric techniques, analyses according to the Adair's formalism show that at least one of the intermediate steps of ligation has a positive enthalpy change, i.e., absorbs rather than emitting heat, indicating that it is entropy rather than enthalpy driven (Bucci, E., et al. 1991. Biochemistry. 30:3195-3199; Bucci, E., et al. 1993. Biochemistry. 32:3519-3526; Johnson, C., et al. 1992. Biochemistry. 31:10074-10082; Johnson, C., et al. 1995. Biophys. Chem. 59:107-117). This phenomenon is confirmed in systems in which the beta82 lysines of human hemoglobin are covalently cross-linked by acylation with dicarboxylic acids of increasing length, namely the fumaryl (four-carbon-long), adipoyl (six-carbon-long), and sebacoyl (10-carbon-long) residues. Consistently in all of the systems here reported, the enthalpy excursions are masked by compensatory entropy changes, which keep the free energy of ligand binding constant for the first three steps of oxygenation. Furthermore, the cooperativity index and the overall oxygen affinity seem to be correlated to the positive enthalpy excursions of the intermediate steps of ligation. Fumaryl-Hb (hemoglobin cross-linked with a fumaryl residue, four carbons) with the lowest absorption of heat has the highest affinity and lowest cooperativity index. Adipoyl-Hb (hemoglobin cross-linked with an adipoyl residue, six carbons) has the highest absorption of heat and the highest cooperativity index. It appears that nonuniform heat release by the intermediates of oxygenation is part of the allosteric phenomena in hemoglobin systems. There is not enough information that would allow assigning these phenomena to the interplay of the various conformations described for hemoglobin besides the classic T (Fermi et al. 1984. J. Mol. Biol. 175:159-174) and R (Shanaan. 1983. J. Mol. Biol. 171:31-59), as listed at the end of the Discussion. The possibility cannot be excluded that entropy-driven steps characterize new conformational transitions still to be described.     

The reversed-flow medio-distal fasciocutaneous island thigh flap: anatomic basis and clinical applications

To investigate changes in retinal pigment epithelial (RPE) cells during wound healing, we evaluated the deposition of newly synthesized extracellular matrix (ECM) over time during wound healing in rat RPE cultures. We also estimated the effect of growth factors on the healing rate and ECM synthesis. After preparing rat RPE cell sheet cultures, we made round 1-mm defects in the cultures. Fibronectin, laminin, and collagen IV synthesis were evaluated with immunocytochemistry every 12 hours after wounding. S-phase cell distribution was analyzed every 12 hours by 5-bromodeoxyuridine uptake. We added either platelet-derived growth factor (PDGF), epidermal growth factor (EGF), or transforming growth factor- beta2 (TGF-beta2) to cultures at concentrations of 1, 10, and 100 ng/mL and immunocytochemically analyzed the effects on ECM and estimated the rate of wound closure. Although approximately 50% closure was achieved 24 hours after wounding, fibronectin deposits first appeared at that time. Laminin and collagen IV were first detected at 36 hours and fibronectin staining had extended toward the wound center. S-phase cells were distributed in concentric rings that moved centripetally over time and corresponded to the leading edge of the area stained with anti-ECM antibodies. TGF-beta2 enhanced ECM deposition, but EGF and PDGF did not. TGF-beta2 decreased the healing rate in a dose-dependent manner, whereas PDGF promoted wound closure. EGF enhanced closure at the highest concentration only. In summary, wound healing in RPE may be initiated when cells at the wound edge slide or migrate toward the wound center, which is followed by cell proliferation and then ECM synthesis. ECM components may be produced in a specific sequence during healing. TGF-beta2 may promote RPE cell differentiation, and PDGF may enhance proliferation during wound healing of the RPE.     

Intravenous leiomyomatosis of the uterus: a clinicopathologic study of 22 cases

Sphingosine-1-phosphate (Sph-1-P) has been implicated as a second messenger in control of cell motility and proliferation (e.g., Sadahira Y, et al., PNAS 89:9686, 1992; Olivera A & Spiegel S, Nature 365:557, 1993). The control mechanism for its synthesis, as catalyzed by sphingosine kinase, is crucial in signal transduction. Synthesis of Sph-1-P in Balb/c 3T3 fibroblasts (A31 variant) is strongly up-regulated by brief treatment of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA). Level of Sph-1-P in PKC-depleted cells is 10-fold higher than in undepleted cells, and a further 5-fold increase occurs after treatment with TPA. In Swiss 3T3 and B16 melanoma cells, Sph-1-P level was unaffected by TPA treatment. Thus, the effect of TPA on Sph-1-P synthesis appears to be cell type-specific.     

Identification of a signaling pathway activated specifically in the somatodendritic compartment by a heparan sulfate that regulates dendrite growth

In two earlier reports we demonstrated that natural heparan sulfate, but not dermatan or chondroitin sulfate glycosaminoglycans, stimulate axonal elongation and inhibit dendrite growth in vitro (Lafont et al., 1992). The latter specific effect on dendrite elongation was reproduced by chemically synthesized heparan sulfates and by SR 80037A, a purified sulfated and hexanoylated heparin fragment (Lafont et al., 1994). Adding radioactive SR 80037A to purified neurons demonstrated the existence, at the neuronal surface, of heparan sulfate-specific and saturable binding sites, suggesting that SR 80037A activates specific signal transduction pathways. In the present study, using rat or mouse neurons from the embryonic cortex, we show that SR 80037A signaling involves one or several G-coupled receptor or receptors, small GTPases rhoA and/or rhoC, and one or several PKCs. We also demonstrate that the rapid soma rounding elicited by SR 80037A does not require protein synthesis but that the long-term effect on dendrite initiation requires protein synthesis in a short period after the addition of the heparan sulfate. Finally, by preparing membranes from the somatodendritic or axonal compartments we demonstrate that the identified signaling pathway is activated by SR 80037A primarily in the somatodendritic compartment and is not sensitive to the addition of a dermatan sulfate glycosaminoglycan that does not induce the axonal phenotype by impairing dendrite initiation and elongation.     

Radiology and spondylarthritis

Radiographs are characteristically required to define the nature of the disease process in spondylarthritis. They need rarely be repeated, except for complications or unusual manifestations of the underlying disease. To date, new techniques of radio-imaging have provided only minimal advantages, if any. (Berkowitz et al, 1991; Docherty et al, 1992; Gibbon, 1992; Ralston et al, 1992; Deyo, 1994; Jensen et al, 1994). The plain radiograph is still pivotal to our understanding of the disease.     

Practical study of the correlation between the shape of tumoral vessels (Folberg) and the histologic type of uveal malignant melanoma (Callender)

A practical study was carried out on 20 cases of uveal malignant melanoma (UMM), dealing with the histological aspect (according to Callender's classification modified by McLean et al. in 1983) and the shape of the tumor vessels (according to Folberg 1992). A correlation was reported in the literature between the histopathological type of UMM and the vascular aspect. Folberg et al. (1992) reported that a correlation exists between the histopathologic type of UMM and the aspect of the vascularization. Folberg et al. (1992) reported that in spindle cell UMM parallel or normal vessels prevail: in epitheloidal shaped cell UMM arc- or ring-shaped vessels are prevalent; and in mixed MMU parallel, ring- and arc-shaped vessels and networks were noticed. The present study aimed at simplifying the correlation between the histopathologic type and vascularization in 5 categories with an easier applicability in the ophthalmologic practice.     

Prevalence of Posttraumatic Stress Disorder in Persons With Spinal Cord Injuries: The Mediating Effect of Social Support.

Objectives: To evaluate the prevalence of posttraumatic stress disorder (PTSD) and to identify risk factors of PTSD in persons with spinal cord injury (SCI). Main Outcome Measures: PTSD and social support were assessed by using the Harvard Trauma Questionnaire (R. F. Mollica et al., 1992) and the Crisis Support Scale (S. Joseph, W. Yule, R. Williams, & B. Andrews, 1993). Participants: One hundred sixty-eight persons with SCI, who were an average of 14 years after injury, filled in the questionnaire. Results: The prevalence of PTSD was 7.1%. Risk factors for PTSD included complete injury, being single, and low level of social support. Conclusions: The prevalence of PTSD after SCI is similar to that in the general population. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons

Astrocytes exhibit a form of excitability and communication on the basis of intracellular Ca2+ variations (Cornell-Bell et al., 1990; Charles et al., 1991) that can be initiated by neuronal activity (Dani et al., 1992; Porter and McCarthy, 1996). A Ca2+ elevation in astrocytes induces the release of glutamate (Parpura et al., 1994; Pasti et al., 1997; Araque et al., 1998;Bezzi et al., 1998), which evokes a slow inward current in neurons and modulates action potential-evoked synaptic transmission between cultured hippocampal cells (Araque et al., 1998), suggesting that astrocytes and neurons may function as a network with bidirectional communication. Here we show that a Ca2+ elevation in astrocytes increases the frequency of excitatory as well as inhibitory miniature postsynaptic currents (mPSCs), without modifying their amplitudes. Thapsigargin incubation, microinjection of the Ca2+ chelator BAPTA, and photolysis of the Ca2+ cage NP-EGTA demonstrate that a Ca2+ elevation in astrocytes is both necessary and sufficient to modulate spontaneous transmitter release. This Ca2+-dependent release of glutamate from astrocytes enhances mPSC frequency by acting on NMDA glutamate receptors, because it is antagonized by D-2-amino-5-phosphonopentanoic acid (AP5) or extracellular Mg2+. These NMDA receptors are located extrasynaptically, because blockage specifically of synaptic NMDA receptors by synaptic activation in the presence of the open channel blocker MK-801 did not impair the AP5-sensitive astrocyte-induced increase of mPSC frequency. Therefore, astrocytes modulate spontaneous excitatory and inhibitory synaptic transmission by increasing the probability of transmitter release via the activation of NMDA receptors.     

Occurrence versus moderation of the automatic attitude activation effect: Reply to Fazio.

In this reply to R. H. Fazio's (see record 1993-32136-001) commentary on the article by J. A. Bargh et al (see record 1992-33847-001), the main purposes and findings of that research are reviewed. This reply presents new data that replicates the original findings of J. A. Bargh et al regarding the conditions under which reliable moderation of automatic attitude activation by speed is more versus less likely. It also responds to the renditions of them by H. Fazio's and J. A. Bargh et al. This reply argues that automatic attitude activation is a pervasive phenomenon and that moderation by attitude speed may be a more limited tendency. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibition of L- and P-selectin by a rationally synthesized novel core 2-like branched structure containing GalNAc-Lewisx and Neu5Acalpha2-3Galbeta1-3GalNAc sequences

The selectins interact in important normal and pathological situations with certain sialylated, fucosylated glycoconjugate ligands containing sialyl Lewisx(Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)GlcN Ac). Much effort has gone into the synthesis of sialylated and sulfated Lewisxanalogs as competitive ligands for the selectins. Since the natural selectin ligands GlyCAM-1 and PSGL-1 carry sialyl Lewisxas part of a branched Core 2 O-linked structure, we recently synthesized Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-6(SE-3Galbeta1++ +-3)GalNAc1alphaOMe and found it to be a moderately superior ligand for L and P-selectin (Koenig et al. , Glycobiology 7, 79-93, 1997). Other studies have shown that sulfate esters can replace sialic acid in some selectin ligands (Yeun et al. , Biochemistry, 31, 9126-9131, 1992; Imai et al. , Nature, 361, 555, 1993). Based upon these observations, we hypothesized that Neu5Acalpha2-3Galbeta1-3GalNAc might have the capability of interacting with L- and P-selectin. To examine this hypothesis, we synthesized Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-6(Neu5Acalpha2++ +-3Galbeta1-3)-GalNAc alpha1-OB, which was found to be 2- to 3-fold better than sialyl Lexfor P and L selectin, respectively. We also report the synthesis of an unusual structure GalNAcbeta1-4(Fucalpha1- 3)GlcNAcbeta1-OMe (GalNAc-Lewisx-O-methyl glycoside), which also proved to be a better inhibitor of L- and P-selectin than sialyl Lewisx-OMe. Combining this with our knowledge of Core 2 branched structures, we have synthesized a molecule that is 5- to 6-fold better at inhibiting L- and P-selectin than sialyl Lewisx-OMe, By contrast to unbranched structures, substitution of a sulfate ester group for a sialic acid residue in such a molecule resulted in a considerable loss of inhibition ability. Thus, the combination of a sialic acid residue on the primary (beta1-3) arm, and a modified Lexunit on the branched (beta1-6) arm on an O-linked Core 2 structure generated a monovalent synthetic oliogosaccharide inhibitor superior to SLexfor both L- and P-selectin.     

Diabetic vascular complications

1. Diabetic vascular complications can be arbitrarily divided into micro- and macrovascular complications, the major microvascular complications being nephropathy, retinopathy and neuropathy. Macrovascular complications are due to accelerated atherosclerosis and include ischaemic heart disease, cerebrovascular disease and peripheral vascular disease. 2. It is postulated that metabolic and haemodynamic factors interact leading to the development of diabetic vascular complications. 3. Advanced glycation appears to be an important pathway in the pathogenesis of diabetic complications with evidence that the inhibitor of this process, aminoguanidine, attenuates the development of a range of diabetic vascular complications. 4. The results of experimental studies have led to large-scale clinical trials of various therapeutic agents that act to interfere with the metabolic and haemodynamic pathways implicated in the progression of diabetic complications.