Interestingly, less intracellular

doxorubicin was detected after incubation with unsensitive HER2 targeted doxorubicin-loaded liposomes than reduction-sensitive targeted liposomes, further demonstrating the need for multifunctional liposomes. A combination of enhanced uptake and reduction-sensitivity was also done using reduction-detachable PEG and TAT [298]. Cleavage of DOPE-S-S-PEG5000 allowed unmasking of Inhibitors,research,lifescience,medical DOPE-PEG1600-TAT and superior uptake of calcein in vitro over uncleavable TAT-modified liposomes together with stability in the presence of serum. Reduction-sensitive liposomes have also been used for gene delivery and a linear correlation between Inhibitors,research,lifescience,medical intracellular glutathione content and transfection efficiency has been recently demonstrated [299]. 6. Intracellular Delivery Internalization of anticancer drugs by cancer cells in tumors was shown to be a barrier to be overcome for cancer therapy [98, 101]. The use of internalization modifications at the liposomal surface or

exposed after release of a PEG corona in the tumor-environment for active transport into cells and even subcellular delivery increased therapeutic activity [7, 17, 96, 300]. The influence of lipid composition on drug release and internalization, endosomal escape strategies, and mitochondria targeting is discussed below (Figure Inhibitors,research,lifescience,medical 4). Figure 4 Strategies for intracellular delivery. Steps for intracellular delivery: (1) Stimuli-sensitive activation/unmasking of internalization Inhibitors,research,lifescience,medical moiety, (2) Cancer cell-specific endocytosis, (3) Endosomal escape and/or therapeutic agent release after activation … 6.1. Importance of Lipid Inhibitors,research,lifescience,medical Composition The presence of cholesterol or rigid saturated lipids (DSPC, HSPC) stabilizes the liposomal membrane against liposomal dissociation by plasma proteins and limits drug leakage, and thus most drug-loaded liposomes include cholesterol in the lipid bilayer [45, 288, 301]. These lipids have high gel-to-liquid crystalline phase crotamiton transition

temperatures (55–58°C) compared to physiological temperature (37°C) which prevents PF-04691502 price coexistence of the two phases and contributes to improved drug pharmacokinetics [13, 45, 302]. In some studies, the couple sphingomyelin/cholesterol is used to further rigidify the membrane through hydrogen bonding [303]. However, cholesterol inclusion can decrease drug loading. Indeed, paclitaxel loading decreased form 99.3% at a 5% molar content of cholesterol to 66.5% at 17% cholesterol content and 6.2% at a 37% molar content as a result of the hindered drug penetration in the increasingly rigid lipid bilayer [304]. The lipid composition is also important for the choice of the PEG-lipid conjugate used for PEGylation. Indeed, Kusumoto et al.

EGFR inhibitors have

exhibited single agent activity, and seem to synergize very well with standard Fostamatinib chemotherapy except for cetuximab and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX). Preliminary data suggests that EGFR inhibitors have similar effectiveness to vascular endothelial growth factor (VEGF) inhibitors in the first line setting. Skin toxicity remains the main limiting factor for the utilization of EGFR inhibitors, but strategies including the use of agents such as minocycline or doxycycline added to topical care seem to limit the severity of the rash. Key Words: Epidermal growth factor inhibitors (EGFR inhibitor), metastatic colorectal cancer (mCRC), cetuximab, panitumumab, Inhibitors,research,lifescience,medical KRAS, targeted therapy Introduction Colorectal cancer (CRC) is the 2nd leading cause Inhibitors,research,lifescience,medical of cancer-related death in the Western population and results in approximately 50,000 deaths annually in the United States (1). The incidence and mortality has decreased from 1999-2006, which is attributed

Inhibitors,research,lifescience,medical to improvements in surgical and adjuvant therapy as well as increasing use of screening methods leading to earlier detection. About 20% of patients present with metastatic colorectal cancer (mCRC) and untreated, this group has a median overall survival (OS) of 7 months (2) and with therapy, a 5-year survival rate Inhibitors,research,lifescience,medical of 10% (3). The most common sites of metastasis are liver, lymph nodes, lung, and peritoneum. Recent advances in the understanding of tumor biology and genetics has paved the way for targeted therapies and led to improvements in the efficacy of cytotoxic regimens. 5-fluorouracil (FU) has been available for use in CRC for over 60 years and eight additional agents have been approved since Inhibitors,research,lifescience,medical 1996, five of which are targeted therapies. Epidermal growth factor receptor-the target The epidermal growth factor receptor (EGFR) is a 170 kDa receptor tyrosine kinase, and a member of the human epidermal growth factor receptor (HER) or ErbB family. EGFR is also known as the type 1 receptor tyrosine

kinase or ErbB1/HER1. The other members of the family include ErbB2 (HER2/neu), ErbB3 (HER3) and ErbB4 (HER4) (4). EGF is a potent epithelial mitogen in the gastrointestinal tract and can stimulate epithelial proliferation in the neonatal intestine. Furthermore, it can enhance the growth DNA ligase of primary colon epithelial cell cultures (4). Most epithelial cancers express EGFR and this growth factor receptor was the first to be proposed as a target for cancer therapy (5). The first anti-EGFR drugs were developed in 1980s and it took over 20 years for the first one to become commercially available. The EGF receptor is composed of an extracellular ligand-binding domain, a transmembrane segment and an intracellular tyrosine kinase domain.

This can signal cancer cell proliferation, inhibition of apoptosis, activation of invasion and stimulate tumor-induced neovascularization. Its overexpression or constitutive action has been shown to affect signaling cascades in carcinogenesis, most importantly the RAS/RAF/MAPK pathway (5). The RAS proteins are serine-threonine kinases that are activated downstream of EGFR. EGF, EGFR and TGF-α are expressed in 60-80% of colorectal cancers (4,6,7) and strong expression has been associated with decreased disease-free survival and overall survival (8-11). Cetuximab and panitumumab Mechanisms of action Inhibitors,research,lifescience,medical and drug

overview The mechanisms of action for EGFR inhibitors include the following properties: (I) Interference with cell-cycle progression with arrest in the G1 phase prior to DNA synthesis; (II) Antiangiogenic activity through downregulation of angiogenic factor secretion such as vascular endothelial growth factor (VEGF); (III) Inhibition of tumor cell Inhibitors,research,lifescience,medical invasion and metastasis by decreasing matrix metalloproteinase production and; (IV) Promoting apoptosis which enhances the effectiveness of cytotoxic therapy (12). Cetuximab is a chimeric monoclonal IgG-1 antibody Inhibitors,research,lifescience,medical that was initially approved for treatment in refractory mCRC by the Food and Drug Administration (FDA) in February 2004. In

July 2012 it was eventually approved in combination with 5-FU, leucovorin and irinotecan (FOLFIRI) in the first line treatment of patients with mCRC based on a phase III trial by van Cutsem et al. (13) (see further discussion in Cetuximab chapter below). Cetuximab binds to EGFR in Inhibitors,research,lifescience,medical its inactive form with higher affinity than either EGF or TGF-α and competes with other ligands by occluding the ligand-binding region and thereby ligand-induced EGFR tyrosine kinase inactivation (14). Direct inhibition of EGFR activation Inhibitors,research,lifescience,medical is considered the primary

mechanism for antitumor activity for cetuximab, but other mechanisms including antibody-dependent cellular cytotoxicity (ADCC) and receptor this website internalization are likely to play an important either role as well (see Figure 1). ADCC is dependent on interactions between the cellular FcᵧR and the monoclonal antibody, which triggers innate immunologic responses involving natural killer cells, monocytes, macrophages, activated T-lymphocytes and granulocytes. Patients with certain FcᵧR polymorphisms (FCGR2A-H131R and FCGR3A-V158F) have been shown to have higher response rates to cetuximab compared to those without this polymorphism (15). The clinical contribution of the ADCC effect is unclear and continues to be subject of investigation including methods to amplify its signal to clinical relevance, such as with lenalidomide. Receptor internalization downregulates the number of available cell surface receptors and could therefore affect EGFR activation (16).

Localization of melatonin receptors Since 1987, the use of [125I]MEL as a ligand with a high specific activity has permitted studies on the localization of MEL receptors (or more exactly binding sites) of the MEL-1 family (MT1, MT2, and Mel1c).The binding sites appear to be widespread in vertebrates. Comparative distribution studies reveal the presence of MEL binding sites in the brain of five P450 inhibitor solubility dmso vertebrate classes (fish, amphibian, reptiles, birds, and mammals). The most relevant feature is that the distribution of MEL Inhibitors,research,lifescience,medical binding sites in lower vertebrates is much larger

than in mammals, and they are consistently found in areas associated with retinorecipient and integrative structures of the visual system.43 In mammals the situation is more contrasted. Contrary to what, is generally claimed, in mammals, MEL receptors are Inhibitors,research,lifescience,medical also present in a large number of structures. They have been described in more than 110 brain structures, among them the internal granular layer and the external plexiform layer of the olfactory bulb, lateral septum, scptohippocampal nucleus, caudate putamen bed nucleus of the

stria terminalis, SCN, mediobasal hypothalamic nuclei, paraventricular nuclei of the hypothalamus, paraventricular nuclei of the thalamus, intergeniculate leaflet, central and medial amygdaloid nucleus, inferior colliculus, fasciculus retroflexus, substantia nigra, and frontal, orbitofrontal, and parietal cortex.44-46 Inhibitors,research,lifescience,medical However, Inhibitors,research,lifescience,medical a great variability has been noted in the number and location of labeled structures among the species, as well as large differences in receptor den sity between structures and in the same structures between species. Few structures are common, even among species from the same family,44 and very probably this should be correlated either

to the numerous photoperiodic responses, which are different from one species to another, or to the many different, effects described for MEL (see below). Among all these structures, the pituitary PT, which shows the highest density Inhibitors,research,lifescience,medical of MEL receptors and is the only structure found consistently labeled old in all mammals so far studied, and the SCN, which contains MEL receptors in many species, are considered as two major sites for MEL action (see below). However, it. should also be pointed out that MEL receptors/binding sites have been identified in numerous peripheral organs. The role of these receptors has not yet been extensively studied, but their presence explains the reported direct action of MEL, for example, on blood vessels47-49 and on cell-mediated and humoral immune function50 on Leydig and luteal cells.51 Its also indicates that the MEL message can be read at different levels of the organism, which should be taken into account when the potential therapeutic properties of MEL or MEL analogues are considered, especially as specific binding sites have been reported in several neoplastic tissues.

Activation of genomic and/or nongenomic signaling pathways contributes to the regulation of cell proliferation and differentiation [3]. Estrogens control the production and activity of components in the cell cycle progression, including cyclines, cyclin-dependent kinases, and their inhibitors [4]. Additionally, direct cancerogenic effects of estrogens can occurs via formation of electrophilic, redox-active estrogen ortho-quinones from catechol estrogens. The concurrent formation of reactive oxygen species and

superoxide anions can damage DNA and cellular proteins [5]. In serum and tissues like the female breast, estrogens are mainly present Inhibitors,research,lifescience,medical in their inactive sulfated form [5, 6]. The important precursor for E2 in the “sulfate pathway” is inactive estrone-3-sulfate (E1S). This is the most abundant estrogen in women at all ages as well as in men. Levels of E1S in blood are 5–10-fold higher than that of unconjugated estrogens, estrone (E1), estradiol (E2), and estriol (E3). As it has also a longer half-life than E2, it is considered Inhibitors,research,lifescience,medical as storage form for estrogens in some organs, for example, breast, from where active E1 is liberated Inhibitors,research,lifescience,medical by removal of the sulfate through STS [7, 8]. To create E2, E1S is taken up into the cells. There, after the removal of sulfate, E1 is reduced by reductive members of the superfamily of 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) to form E2. Oxidative 17β-HSDs catalyze the conversion

of E2 to E1. Reductive 17beta-HSDs Inhibitors,research,lifescience,medical also inactivate androgens and catalyze also the formation of other estrogens, for example, 5alpha-androstenediol. Since 17beta-HSDs modulate the concentration of active estrogens and androgens, inhibitors of these enzymes may be applied in cancer therapy [9, 10] (Figure 1). Figure 1 Estrone sulfate (E1S), androstenediol-sulfate (Adione-S), and dehydroepiandrosterone-sulfate (DHEA-S) are taken up into cells by organic anion transporting polypeptides (OATPs) and other transporters from the SLC-family. The

“sulfatase pathway,” … Polar estrogen sulfates, Cediranib particularly, E1S, are taken up into cells by specific transport proteins from different families Inhibitors,research,lifescience,medical of SLC transporters including the family of heptaminol organic anion transporters SLC21 or organic anion transporting polypeptides (OATPs). Within this concept, transporters from the OATP (SLC21) family such as OATP1A2, OATP1B3, OATP2B1, and OATP3A1 contribute to the cellular accumulation of E1S [11, 12], while ABC-efflux pumps from the MRP-family (ABCC1 and ABCC2), and the breast-cancer resistance protein (BCRP, ABCG2) mediates the efflux of E1S from the cells [13] (Figure 2). Uptake, biotransformation and excretion are transcriptionally regulated by nuclear receptors, for example, the pregnane X receptor. Furthermore, the variability in the expression levels and gene variants of transporters and enzymes can affect expression and function. These mechanisms may therefore influence the susceptibility of individuals to certain malignancies [14, 15].

BMS345541 lateralization for visuospatial memory in the latter group was to the right, the left, or exhibiting a bilateral representation. Means, standard deviations, t-tests, and effect sizes are summarized in Table 3. Children with language lateralized to the left hemisphere showed significantly better vocabulary and nonword reading skills than children

for whom language was not lateralized to the left hemisphere. However, phonological short-term memory was unrelated to language lateralization (see Table 3). It has been proposed that the development of absolute skill might drive lateralization (Holland et al. 2007; Yamada et al. Inhibitors,research,lifescience,medical 2010). In the case of vocabulary, this would mean that the number of words you know is crucial,

regardless of age. This was not the case. When we repeated the analyses with raw scores for vocabulary (Language Left: M= 109.34, SD= 18.39; Language Other: M= 99.91, SD= 22.43) and nonword reading (Language Left: M= 37.93, SD= 15.17; Language Other: M= Inhibitors,research,lifescience,medical 32.18, SD= 14.20), we did not find significant differences between groups (vocabulary: t(53) =−1.19, p= .239, r= .16; nonword reading: t(53) =−1.14, p= .260, r= .15). This suggests that children who had language lateralized to the left hemisphere had better vocabulary and nonword reading skills for their age compared with other Inhibitors,research,lifescience,medical children. Figure 3 Scatterplots showing associations between cerebral lateralization and vocabulary knowledge (left panel) and non-word reading (right panel). Open symbols indicate children with language production (LP) and visuospatial memory (VSM) lateralized to different Inhibitors,research,lifescience,medical … Table 3 Means (standard deviations), independent t-tests, and effect Inhibitors,research,lifescience,medical sizes for performance on cognitive and language tests for children with language production lateralized to the left hemisphere (Language Left) or not (Language Other). Discussion

In this study, we assessed cerebral lateralization for language production and visuospatial memory in a group of 60 typically developing children between the ages of six and 16 years. As has been found Org 27569 in fTCD studies in adults (Flöel et al. 2001; Whitehouse and Bishop 2009; Lust et al. 2011a, b; Rosch et al. in press), the majority of children showed left-lateralized activation on the language production task and right-lateralized activation on the visuospatial memory task. Our first aim was to assess whether lateralization changed with age. For the language production task, we did not find any association between the direction or the strength of lateralization and age. This is in agreement with other fTCD studies (Lohmann et al. 2005; Haag et al. 2010; Stroobant et al. 2011), but does not tally with the fMRI work (Gaillard et al. 2000; Holland et al. 2001, 2007; Szaflarski et al. 2006a, b).

2010; Kuenzel et al. 2010), and PDGFA which encodes the prepropeptide PDGF A chain. PDGFA is specifically up-regulated by Th2 class cytokines (Lisak et al. 2007). In our study, this gene was markedly suppressed, pointing to a decrease in the Th2 class cytokine signaling in HCV patients who develop depression. In fact, our data necessitate a closer examination of

Inhibitors,research,lifescience,medical the pretreatment baseline levels of Th1 class and Th2 class cytokines in patients scheduled for IFN-α therapy, as interferon-induced depression may in fact involve a pre-existing imbalance in the host Th1/Th2 levels, rendering certain patients vulnerable to depression. Our study also supports the potential role of TGF-β1 in IFN-related depression. TGF-β1 is mainly secreted by regulatory T cells such as type 1 regulatory T cells and T-helper type 3 cells (Th3) and is thought to be essential for the maintenance of immune SGC-CBP30 mw homeostasis and for the suppression of autoimmunity (Groux et al. 1997; Taylor et al. 2006; Zhang et al. 2006). TGF-β1 is known to Inhibitors,research,lifescience,medical not only promote T-helper type 2 cell (Th2) differentiation Inhibitors,research,lifescience,medical (Barral-Netto et al. 1992) but also to exert a strong inhibitory effect on the production of pro-inflammatory

cytokines such as interferons (IFNs), tumor necrosis factor (TNF-α), and IL-2 (Schmitt et al. 1994; Prud’homme and Piccirillo 2000) (Fig. 1). Recent studies indicate that, TGF-β1 plays a role in the development Inhibitors,research,lifescience,medical of depression by shifting the balance between the pro-inflammatory/anti-inflammatory cytokines seen in this disorder (Myint et al. 2005; Lee and Kim 2006). In fact, recent studies on MDD have shown that significantly lowered pretreatment TGF-β1 levels in the depressed patients increase following antidepressant therapy Inhibitors,research,lifescience,medical (Myint et al. 2005). The decreased baseline levels of TGF-β1 seen within our cohort of HCV patients who ultimately developed depression during treatment, may well follow the same etiology as seen in patients with MDD. Importantly, TGF-β1 has been extensively studied within the context of liver disease, particularly in relation to inflammation and fibrosis (Wynn

and Barron 2010). However, little is known about its role within the context of PEG-IFN+RBV treatment of HCV and its associated side effects. The current study is the first to point to TGF-β1 as having a pivotal role in IFN-related depression. Figure 1 Transforming growth factor-b no (TGF-β) and its effects on a large group of secreted cytokines, with a wide range of functional properties. Importantly, worldwide efforts in genome-wide profiling of the polymorphisms associated with MDD and antidepressant treatment outcomes produced only a handful of the candidate genes. Moreover, even in the largest of these studies, the genome-wide significance was not achieved (see Laje and McMahon 2011; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium 2012, for recent reviews).

Hence diagnoses were poorly comparable. Methods to assess abnormal human behavior were nonexistent. This situation was rather disastrous for research, particularly biological research, dependent as it is on a precise and valid definition of the object of study. Diagnoses at that time were inaccurate, but refined, at least in Rurope, due to

the two dominant philosophies in psychiatry back in those days: phenomenology and psychoanalysis. In order to make Inhibitors,research,lifescience,medical a diagnosis, one was required: to provide a detailed account of the symptomatology of a given patient; to pay due CFTR inhibitor attention to the experiential consequences of the symptoms; to describe in detail the psychogenesis of the disorder, ie, the alleged relationship between the complex: psychological development/personality structure/psychotraumatic event

on the one hand, and the present psychopathology on the other. In 1980, the third edition of Inhibitors,research,lifescience,medical the DSM appeared and the changes it brought about were profound. In a way they signified immense progress. A standardized and operationalized Inhibitors,research,lifescience,medical taxonomy was introduced that gained worldwide acceptance almost overnight by the psychiatric community, clinicians, and researchers alike. However, the price that had to be paid for those benefits was high, in that the diagnostic process coarsened and markedly lost out in terms of sophistication, a statement Inhibitors,research,lifescience,medical that will be clarified in the next section. Is this accusation a fair one? Can a classification system be blamed for shortcomings in the way we make a diagnosis? After all, classification of psychiatric disorders is, or rather ought to be, the end point of the diagnostic process, in which all data concerning symptomatology, causation, and course of a psych opathologi cal condition crystallize in a single construct. In actual practice, however, classification is much

more than that. To a considerable degree classification systems steer the diagnostic process. Psychopathological data tend to be viewed and interpreted in such a way as to Inhibitors,research,lifescience,medical fit as far as possible the diagnostic categories available. The impact of classification on the Non-specific serine/threonine protein kinase diagnostic process is more profound the stricter and more detailed a taxonomic system spells out the diagnostic criteria. The influence that the DSM has exerted on the diagnostic process from the third edition onwards is a case in point. Our trainees learn, as it were, to diagnose with a copy of the DSM in their hand or at least at the back of their mind. That which is not included in the DSM seems to have become almost irrelevant. Since classification impacts on the making of a diagnosis, and since precise and valid diagnoses form the very bedrock of clinical psychopharmacology and biological psychiatry, classification has had and continues to have a profound influence on the development of those disciplines.

106 As pertains to psychosocial interventions,

unfortunately, there are few empirically supported treatments for peer problems in ADHD and related disorders implicating executive functioning.107 Crucially, however, there are empirically supported treatments to aid development of executive functioning that may also be appropriate settings to address social skills.108 These interventions, often delivered in school settings, may be readily combined with adjuvant SST or CBT interventions. There is fruitful work that may be done to directly examine the effects of such training on improved social functioning in this population, Inhibitors,research,lifescience,medical implicating a fairly easily testable change mechanism. Internalizing comorbidities Youth with ASD are also known to experience high rates of internalizing comorbidities, especially clinically significant elevations in anxiety and depressive disorders.103,109 Importantly, associations have been found between anxiety and social deficits in this population.’-110,111 Inhibitors,research,lifescience,medical Clinical and anecdotal observations suggest it may specifically be the awareness of social difficulties that enhances anxiety in adolescents with ASD.112 Additionally, research has implicated a relationship between greater cognitive and verbal abilities, and greater ASD severity, and elevated risk of depression.113

This emerging descriptive research suggests that internalizing Inhibitors,research,lifescience,medical disorders Inhibitors,research,lifescience,medical may play a role in predicting social dysfunction in this population. Promising interventions to specifically address anxiety using CBT in

this population have recently proliferated.114,115 Most of this clinical work has adapted CBT programs to primarily target anxiety reduction114,116,117,118 in children under the age of 14. Collectively, this body of research suggests that internalizing processes may be amenable to intervention in ASD. However, they do not explicitly examine the Rigosertib potential role of anxiety (or other internalizing problems, such as depression) as a mechanism of change in improving Inhibitors,research,lifescience,medical core ASD deficits. In a crucial recent step towards testing the possible mechanistic nature of anxiety in social dysfunction in ASD, White and colleagues119 produced and tested a manualized intervention to treat both of these Phosphatidylinositol diacylglycerol-lyase deficits in this population. Further exploration of this intervention will be essential in teasing out the degree to which decreasing anxiety may act as a mechanism of change in addressing social functioning in ASD. Other potential mechanisms As the consideration of common and unique mechanisms of change in psychosocial interventions for ASD is fairly new, we have focused above only on those that are most promising based on the available literature. We note, however, that there may be several more that are worthy of consideration, whose comprehensive exploration is beyond the scope of this overview.

They probed the interactions between cytokine systems and the hypothalamic-pituitary-adrenal axis (HPA), and suggested that increased cytokine activities may drive the

HPA axis and may underlie the hypercortisolemia found in subpopulations of patients with depression. Most basically, the central element of their hypothesis is that the increased cytokine activity and the activation of acutephase or inflammatory processes in depression is a regulatory abnormality characteristic of depression, rather than a reflection of medical illness. An alternative hypothesis for a role of cytokines Inhibitors,research,lifescience,medical in the pathogenesis of depression is based upon concepts of “sickness behavior.”72-75 According to these models, infection, inflammation, or tissue injury can activate inflammatory processes and induce cytokines that can act locally or systemically to regulate Inhibitors,research,lifescience,medical homeostatic responses. Some of these responses, including those that involve acute-phase processes, occur in the periphery, while others involve (direct or indirect) actions of cytokines Inhibitors,research,lifescience,medical on the central nervous system. Some of these central nervous system-mediated effects, such as fever, are physiological, while others arc behavioral. The latter include a number of nonspecific behaviors associated with illness and

injury such as decreased exploratory activity, decreased sexual activity, anorexia, and changes in sleep structure. Studies of the behavioral pharmacology of the cytokines in experimental animals demonstrate that they can, in fact, cause these behaviors; however, questions

remain about the mechanisms through which the Inhibitors,research,lifescience,medical induction of cytokines in the periphery can cause centrally mediated effects. Nevertheless, this hypothesis proposes that depression can occur when cytokine-mediated processes are induced by illness or injury, and that the depressions that arise through these mechanisms are pathological variants of Inhibitors,research,lifescience,medical normal and adaptive sickness behaviors. As discussed above, it is possible to distinguish between two distinct cytokinc-rclatcd theories of depression, one in which the induction of cytokines occurs spontaneously as a result of regulatory deficits intrinsic to the depressive illness, and the other in which they arise in the context of medical illness. These models may, however, be many poles in a continuum. For example, cytokine-mediated processes initiated by illness could, in principle, remain activated after illness as a result of a failure in restorative mechanisms. Alternatively, regulatory abnormalities may allow for the extensive induction of cytokines by minor illness or injury. Thus, it is possible to propose a series of plausible cytokine theories of depression. The important question is, of course, whether there is empirical check details evidence to support any of them.