Nasogastric tube feeding in line with new dietetic guidelines for the treatment of anorexia nervosa in a specialist children and adolescent inpatient unit: a case series.

BACKGROUND: The present study reports a case series where three adolescent patients with anorexia nervosa (AN) (two cases with typical AN and one case atypical AN) received nasogastric tube feeding under restraint in line with new dietetic clinical guidelines. METHODS: Three cases were chosen out of 61 admitted patients over the period of 1 year who were fed via a nasogastric tube under restraint in a specialist eating disorders unit for children and adolescents. These cases were chosen to highlight a range of clinical scenarios that clinicians may encounter. They also represent clinical scenarios where decisions to feed patients under restraint were rendered more complex by additional concerns. RESULTS: Despite the complexity of the cases, all patients tolerated the feeds well and were discharged home eating solid food. CONCLUSIONS: The decision to feed a patient against their will is never an easy one. Sadly, there have been some recent high-profile deaths of adult patients on medical wards where treatment opinion was not considered, and the patient received no or minimal nutrition when awaiting specialist treatment. Dietetic guidelines have been published to help inform clinicians for whom feeding under restraint may be out of the scope of their daily practice. This case series highlights clinical scenarios that illustrate the utility of the guidelines, which we hope will support clinicians when making, potentially lifesaving decisions in children and young people.

The development of consensus-based guidelines for dietetic practice in nasogastric tube feeding under restraint for patients with anorexia nervosa using a modified Delphi process.

INTRODUCTION: Nasogastric tube feeding against a person's will, under restraint, can be a lifesaving intervention for patients with severe anorexia nervosa. Dietetic guidelines have been developed to support dietitians in this specialised area. METHODS: A modified Delphi process was used in the development of the guidelines; stage 1, initial stakeholders created a draft; stage 2, creation of the working group; stage 3, comments and feedback on draft; stage 4, final draft agreed; stage 5, external review from Psychiatrists, patients and carers; stage 6, endorsement. Specialist mental health dietitians working in both adult and Child and Adolescent Mental Health Services (CAMHS) across four countries contributed to the development of the consensus guidelines. RESULTS: New guidance is outlined specifically for NGT feeding under restraint, which details the process, rate and volume of feed to comply with lawful guidance. CONCLUSIONS: Clinical guidelines were developed for dietitians treating patients with anorexia nervosa, using a modified Delphi process, incorporating both expert opinion and all available evidence. The guidance provides new information to dietitians and clinicians in how to enterally feed patients under restraint where none previously existed.

The P2X7 receptor antagonist Brilliant Blue G reduces serum human interferon-γ in a humanized mouse model of graft-versus-host disease.

Graft-versus-host disease (GVHD) remains a major problem after allogeneic haematopoietic stem cell transplantation, a curative therapy for haematological malignancies. Previous studies have demonstrated a role for the adenosine triphosphate (ATP)-gated P2X7 receptor channel in allogeneic mouse models of GVHD. In this study, injection of human peripheral blood mononuclear cells (PBMCs) into immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (NOD-SCID-IL)-2Rγnull (NSG) mice established a humanized mouse model of GVHD. This model was used to study the effect of P2X7 blockade in this disease. From five weeks post-PBMC injection, humanized mice exhibited clinical signs and histopathology characteristic of GVHD. The P2X7 antagonist, Brilliant Blue G (BBG), blocked ATP-induced cation uptake into both murine and human cells in vitro. Injection of BBG (50 mg/kg) into NSG mice did not affect engraftment of human leucocytes (predominantly T cells), or the clinical score and survival of mice. In contrast, BBG injection reduced circulating human interferon (IFN)-γ significantly, which was produced by human CD4+ and CD8+ T cells. BBG also reduced human T cell infiltration and apoptosis in target organs of GVHD. In conclusion, the P2X7 antagonist BBG reduced circulating IFN-γ in a humanized mouse model of GVHD supporting a potential role for P2X7 to alter the pathology of this disease in humans.

Two-stroke scooters are a dominant source of air pollution in many cities.

Fossil fuel-powered vehicles emit significant particulate matter, for example, black carbon and primary organic aerosol, and produce secondary organic aerosol. Here we quantify secondary organic aerosol production from two-stroke scooters. Cars and trucks, particularly diesel vehicles, are thought to be the main vehicular pollution sources. This needs re-thinking, as we show that elevated particulate matter levels can be a consequence of 'asymmetric pollution' from two-stroke scooters, vehicles that constitute a small fraction of the fleet, but can dominate urban vehicular pollution through organic aerosol and aromatic emission factors up to thousands of times higher than from other vehicle classes. Further, we demonstrate that oxidation processes producing secondary organic aerosol from vehicle exhaust also form potentially toxic 'reactive oxygen species'.

Russian wheat aphids (Diuraphis noxia) in China: native range expansion or recent introduction?

In this study, we explore the population genetics of the Russian wheat aphid (RWA) (Diuraphis noxia), one of the world's most invasive agricultural pests, in north-western China. We have analysed the data of 10 microsatellite loci and mitochondrial sequences from 27 populations sampled over 2 years in China. The results confirm that the RWAs are holocyclic in China with high genetic diversity indicating widespread sexual reproduction. Distinct differences in microsatellite genetic diversity and distribution revealed clear geographic isolation between RWA populations in northern and southern Xinjiang, China, with gene flow interrupted across extensive desert regions. Despite frequent grain transportation from north to south in this region, little evidence for RWA translocation as a result of human agricultural activities was found. Consequently, frequent gene flow among northern populations most likely resulted from natural dispersal, potentially facilitated by wind currents. We also found evidence for the long-term existence and expansion of RWAs in China, despite local opinion that it is an exotic species only present in China since 1975. Our estimated date of RWA expansion throughout China coincides with the debut of wheat domestication and cultivation practices in western Asia in the Holocene. We conclude that western China represents the limit of the far eastern native range of this species. This study is the most comprehensive molecular genetic investigation of the RWA in its native range undertaken to date and provides valuable insights into the history of the association of this aphid with domesticated cereals and wild grasses.

The human P2X7 receptor and its role in innate immunity.

The human P2X7 receptor is a two-transmembrane ionotropic receptor which has a ubiquitous distribution and is most highly expressed on immune cells. In macrophages and similar myeloid cells primed by lipopolysaccharide (LPS), activation of P2X7 by extracellular ATP opens a cation channel/pore allowing massive K+ efflux associated with processing and secretion of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18. A variety of other downstream effects follows P2X7 activation over several minutes including shedding of certain surface molecules, membrane blebbing, microvesicle/exosome release and apoptosis of the cell. High concentrations of ATP (>100 µM) are required to activate P2X7 but it remains unclear where these levels exist, other than in inflammatory foci or confined spaces such as in bone. A variety of potent selective antagonists of P2X7 activation have recently become available, allowing clinical trials to be undertaken in inflammatory and immune-mediated disorders. Proteomic studies have shown that P2X7 exists as a large multiprotein complex which includes non-muscle myosin heavy chain and other elements of the cytoskeleton. In the absence of its ATP ligand and serum, P2X7 has an alternate function in the recognition and phagocytosis of non-opsonized foreign particles, including bacteria and apoptotic cells. The P2RX7 gene has many polymorphic variants and isoforms which increase or decrease function of the receptor. Genetic association studies have linked loss-of-function polymorphisms with reactivation of latent tuberculosis as well as symptomatic infection with certain other obligate intracellular pathogens. The many roles involving P2X7 suggest that this receptor is essential to fundamental aspects of the innate immune response.

Ozonolysis of maleic acid aerosols: effect upon aerosol hygroscopicity, phase and mass.

The hygroscopicity and mass loss of aerosols initially composed of maleic acid have been investigated before and after reaction with ozone. The phase of the aerosol, solid or aqueous, during the reaction with ozone strongly affects the composition of the processed aerosol. Furthermore the loss of aerosol mass, via the production of volatile ozonolysis products, does not occur until the processed aerosol has existed as an aqueous phase aerosol. The loss rate of the aerosol mass appears to follow unimolecular first order kinetics which is consistent with the rate determining step being the cleavage of a weak hydroperoxide, or peroxide, bond (approximately 104 kJ mol(-1)). This speculative rate determining step, which is not based on chemical analysis, is possibly a universal feature in the ozonolysis of organic aerosol containing the alkene functionality.

Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis.

Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X(7), encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X(7) has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores +/-2.429; P=0.015) between the derived C(+)G(-) allele (f=0.68; OR=2.06; 95% CI: 1.14-3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0-4.25; 0.004

Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis.

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Apolipoprotein E, cholesterol metabolism, diabetes, and the convergence of risk factors for Alzheimer's disease and cardiovascular disease.

High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E epsilon4 (APOE epsilon4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Abeta clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE epsilon4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE epsilon4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.

Enhancement of adenoviral gene transfer to adult rat cardiomyocytes in vivo by immobilization and ultrasound treatment of the heart.

Direct injection of adenoviral vectors into ventricular myocardium in vivo produces local transfection of cells including cardiomyocytes. The use of vectors coexpressing GFP with the gene of interest allows subsequent identification of transfected myocytes isolated from the heart some days later, and examination of their function in cell bath experiments. We have injected vectors for antisense to phospholamban, or a control virus for expression of GFP only, into adult rat heart in vivo and then removed the heart and isolated ventricular myocytes 7 days later. Brief immobilization of the ventricle during and after injection using a haemoclip increased the number of transfected rod-shaped, viable myocytes from 1.7 +/- 0.8% (n = 8) to 5.6 +/- 0.8% (n = 9). This was further increased to 13.2 +/- 1.1% (n = 8) by the application of ultrasound pulses to the site before and after injection. Phospholamban antisense increased contraction amplitude and accelerated myocyte relengthening or decline of the Ca(2+) transient in transfected myocytes, while GFP control did not. Qualitative and quantitative effects of phospholamban downregulation were comparable between in vivo and in vitro transfections. This technique will have a number of uses, including production of transfected myocytes without the problem of culture-induced changes in contractility.

Clustering of related individuals in a population of the Australian lizard, Egernia frerei.

Stable social aggregations are rarely recorded in lizards, but have now been reported from several species in the Australian scincid genus Egernia. Most of those examples come from species using rock crevice refuges that are relatively easy to observe. But for many other Egernia species that occupy different habitats and are more secretive, it is hard to gather the observational data needed to deduce their social structure. Therefore, we used genotypes at six polymorphic microsatellite DNA loci of 229 individuals of Egernia frerei, trapped in 22 sampling sites over 3500 ha of eucalypt forest on Fraser Island, Australia. Each sampling site contained 15 trap locations in a 100 x 50 m grid. We estimated relatedness among pairs of individuals and found that relatedness was higher within than between sites. Relatedness of females within sites was higher than relatedness of males, and was higher than relatedness between males and females. Within sites we found that juvenile lizards were highly related to other juveniles and to adults trapped at the same location, or at adjacent locations, but relatedness decreased with increasing trap separation. We interpreted the results as suggesting high natal philopatry among juvenile lizards and adult females. This result is consistent with stable family group structure previously reported in rock dwelling Egernia species, and suggests that social behaviour in this genus is not habitat driven.

Beta-adrenoceptor subtype dependence of chronotropy in mouse embryonic stem cell-derived cardiomyocytes.

Cardiomyocytes derived from embryonic stem cells (ESCM) have potential both as an experimental model for investigating cardiac physiology and as a source for tissue repair. For both reasons it is important to characterise the responses of these cells, and one of the key modulators of contraction is the beta-adrenergic system. We therefore undertook a detailed study of the response of the spontaneous beating rate of ESCM to beta-adrenoceptor (betaAR) stimulation. Embryoid bodies (EBs) were generated from murine ES line E14Tg2a by the hanging drop method, followed by plating. Spontaneously beating areas were seen starting from 9-14 days after differentiation: the experiments described here were performed on EBs between developmental day 19 and 48. Beating cell layers were seeded with charcoal to allow tracking of movement by a video-edge detection system. Experiments were performed in physiological medium containing 1 mM Ca2+ at 37 degrees C. Isoprenaline (Iso) increased beating rate with an EC50 value of 52 nM. Iso (0.3 microM) increased basal rate from 67 +/- 7 beats per minute (bpm) to 138 +/- 18 bpm, P < 0.001, n = 22. At earlier developmental time points the response to Iso was not maintained through 5 min exposure; this spontaneous desensitisation only being observed before day 36. A repeat application of Iso after a wash period of 20 min produced reproducible effects on beating rate. Subtype dependence of the betaAR response was determined by comparing an initial response with a second in the presence of selective beta1- or beta2AR antagonists. In the presence of the specific beta1AR-blocker CGP 20712A (300 nM) the increase in rate with Iso was reduced from 207 +/- 42% of basal to 128 +/- 13%, P < 0.01. With the beta2AR-blocker ICI 118,551 (50 nM) there was no significant change in Iso response. Exposure to the muscarinic agonist, carbachol (10 microM), inhibited the increase in frequency mediated by isoprenaline, but had mixed stimulatory and inhibitory effects on basal rate. This study extends the characterisation of ESCM as a preparation for studying receptor pharmacology, and indicates that the beta1AR is the predominant subtype mediating increases in contraction rate in murine ESCM.

Genetics, lifestyle and the roles of amyloid beta and oxidative stress in Alzheimer's disease.

This paper reviews a wide range of recent studies that have linked AD-associated biochemical and physiological changes with oxidative stress and damage. Some of these changes include disruptions in metal ion homeostasis, mitochondrial damage, reduced glucose metabolism, decreased intracellular pH and inflammation. Although the changes mentioned above are associated with oxidative stress, in most cases, a cause and effect relationship is not clearcut, as many changes are interlinked. Increases in the levels of Abeta peptides, the main protein components of the cerebral amyloid deposits of AD, have been demonstrated to occur in inherited early-onset forms of AD, and as a result of certain environmental and genetic risk factors. Abeta peptides have been shown to exhibit superoxide dismutase activity, producing hydrogen peroxide which may be responsible for the neurotoxicity exhibited by this peptide in vitro. This review also discusses the biochemical aspects of oxidative stress, antioxidant defence mechanisms, and possible antioxidant therapeutic measures which may be effective in counteracting increased levels of oxidative stress. In conclusion, this review provides support for the theory that damage caused by free radicals and oxidative stress is a primary cause of the neurodegeneration seen in AD with Abeta postulated as an initiator of this process.

Autoimmune hemolysis associated with primary biliary cirrhosis responding to ursodeoxycholic acid as sole treatment.

Coombs' positive autoimmune hemolytic anemia (AIHA) has been rarely described in association with primary biliary cirrhosis (PBC). The previously reported cases have responded to treatment with a combination of corticosteroids and ursodeoxycholic acid (UDCA). We report a case of AIHA occurring in association with PBC, which has responded to treatment with UDCA alone. Possible mechanisms of autoimmune hemolysis in this patient include bile salt induced immune dysregulation and direct damage to red cell membranes by bile salts leading to exposure of neoantigens and development of red cell autoantibodies. A trial of UDCA as a single agent should be considered as initial treatment in this rare disorder.

Paranoid psychosis related to mefloquine antimalarial prophylaxis.

Mefloquine is an important antimalarial drug for treatment and prophylaxis of chloroquine-resistant malaria. Its use has been associated with neuropsychiatric side-effects. We report a case of paranoid psychosis associated with mefloquine occurring in a remote part of Papua New Guinea. Adverse reactions and contraindications are discussed. This case underlines the importance of awareness of neuropsychiatric side-effects with mefloquine use and of taking a careful psychiatric history before prescribing mefloquine.

c-Jun N-terminal kinase-interacting protein 1 inhibits gene expression in response to hypertrophic agonists in neonatal rat ventricular myocytes.

G(q)-coupled receptor agonists, such as endothelin-1 (ET-1) and phenylephrine (PE), initiate a hypertrophic response in cardiac myocytes that is characterized by increased expression of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta-MHC), skeletal muscle alpha-actin (SkalphaA) and ventricular myosin light chain-2 (vMLC2). ET-1 and PE activate both the extracellular signal-regulated kinases and c-Jun N-terminal kinases (JNKs) in cardiac myocytes, but the extent to which each contributes to the hypertrophic response is uncertain. Here we have used the JNK-binding domain of JNK-interacting protein 1 (JIP-1), a cytosolic scaffold protein that binds to JNK and inhibits its signalling when overexpressed, to assess the contribution of JNK activation to the hypertrophic response. Expression of JIP-1 inhibited the increase in ANF, beta-MHC, SkalphaA and vMLC2 reporter gene expression in response to ET-1 (by 45-86%) and PE (by 56-60%). However, activation of these reporter genes by PMA, which does not activate JNK significantly in myocytes, was much less affected by overexpression of JIP-1. JIP-1 also failed to inhibit reporter gene activation in response to constitutively active Ras or Raf, but attenuated reporter gene activation induced by a constitutively active mutant of mitogen-activated protein kinase kinase kinase 1 (MEKK1), an upstream kinase that preferentially activates JNKs, by 50%. Overexpression of JIP-1 also significantly reduced the increase in cell area in response to PE from 63% to 56%, but had no effect on the increase in cell size in response to ET-1 (38%). These results suggest that activation of the JNK pathway contributes to the transcriptional and morphological responses to G(q) receptor-coupled hypertrophic agonists.

Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1.

Small guanine nucleotide-binding proteins of the Ras and Rho (Rac, Cdc42, and Rho) families have been implicated in cardiac myocyte hypertrophy, and this may involve the extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and/or p38 mitogen-activated protein kinase (MAPK) cascades. In other systems, Rac and Cdc42 have been particularly implicated in the activation of JNKs and p38-MAPKs. We examined the activation of Rho family small G proteins and the regulation of MAPKs through Rac1 in cardiac myocytes. Endothelin 1 and phenylephrine (both hypertrophic agonists) induced rapid activation of endogenous Rac1, and endothelin 1 also promoted significant activation of RhoA. Toxin B (which inactivates Rho family proteins) attenuated the activation of JNKs by hyperosmotic shock or endothelin 1 but had no effect on p38-MAPK activation. Toxin B also inhibited the activation of the ERK cascade by these stimuli. In transfection experiments, dominant-negative N17Rac1 inhibited activation of ERK by endothelin 1, whereas activated V12Rac1 cooperated with c-Raf to activate ERK. Rac1 may stimulate the ERK cascade either by promoting the phosphorylation of c-Raf or by increasing MEK1 and/or -2 association with c-Raf to facilitate MEK1 and/or -2 activation. In cardiac myocytes, toxin B attenuated c-Raf(Ser-338) phosphorylation (50 to 70% inhibition), but this had no effect on c-Raf activity. However, toxin B decreased both the association of MEK1 and/or -2 with c-Raf and c-Raf-associated ERK-activating activity. V12Rac1 cooperated with c-Raf to increase expression of atrial natriuretic factor (ANF), whereas N17Rac1 inhibited endothelin 1-stimulated ANF expression, indicating that the synergy between Rac1 and c-Raf is potentially physiologically important. We conclude that activation of Rac1 by hypertrophic stimuli contributes to the hypertrophic response by modulating the ERK and/or possibly the JNK (but not the p38-MAPK) cascades.

Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.

Genetic evidence strongly supports the view that Abeta amyloid production is central to the cause of Alzheimer's disease. The kinetics, compartmentation, and form of Abeta and its temporal relation to the neurodegenerative process remain uncertain. The levels of soluble and insoluble Abeta were determined by using western blot techniques, and the findings were assessed in relation to indices of severity of disease. The mean level of soluble Abeta is increased threefold in Alzheimer's disease and correlates highly with markers of disease severity. In contrast, the level of insoluble Abeta (also a measure of total amyloid load) is found only to discriminate Alzheimer's disease from controls, and does not correlate with disease severity or numbers of amyloid plaques. These findings support the concept of several interacting pools of Abeta, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool. The latter may exist in both intracellular and extracellular compartments, and contain the basic forms of Abeta that cause neurodegeneration. Reducing the levels of these soluble Abeta species by threefold to levels found in normal controls might prove to be a goal of future therapeutic intervention.

The amyloid precursor protein of Alzheimer disease in human brain and blood.

Studies of the metabolism and function of the amyloid precursor protein (APP) and its proteolytic fragment A beta in cultured cells, transgenic mice, and post-mortem brain tissue have advanced our understanding of Alzheimer disease (AD). However, the molecular pathogenesis of the disease is still not clear, and we are a long way from finding a cure for the disease. Studies carried out on human platelets and leukocytes have also helped shed light on APP and A beta metabolism and function. Platelet and leukocyte APP isoforms are processed using mechanisms similar to those in neuronal cells to generate A beta and soluble forms of APP. The activation of platelets and leukocytes leads to the secretion of APP and A beta, resulting in higher levels of these proteins in serum. APP and A beta in the circulation may be involved in the regulation of platelet function and in the modulation of immune responses. Because human platelets and lymphocytes produce all forms of APP and secrete amyloidogenic A beta peptides, these tissues may be useful in monitoring responses to therapeutic interventions directed at APP metabolism. Although not of neuronal origin, further studies on the more accessible ex vivo tissues, including platelets and leukocytes and other blood components, may reveal potential peripheral markers for AD and will further our understanding of the molecular pathogenesis of AD.