Pharmacological interaction of drugs with immune receptors: the p-i concept

Drug-induced hypersensitivity reactions have been explained by the hapten concept, according to which a small chemical compound is too small to be recognized by the immune system. Only after covalently binding to an endogenous protein the immune system reacts to this so called hapten-carrier complex, as the larger molecule (protein) is modified, and thus immunogenic for B and T cells. Consequently, a B and T cell immune response might develop to the drug with very heterogeneous clinical manifestations. In recent years, however, evidence has become stronger that not all drugs need to bind covalently to the MHC-peptide complex in order to trigger an immune response. Rather, some drugs may bind directly and reversibly to immune receptors like the major histocompatibility complex (MHC) or the T cell receptor (TCR), thereby stimulating the cells similar to a pharmacological activation of other receptors. This concept has been termed pharmacological interaction with immune receptors the (p-i) concept. While the exact mechanism is still a matter of debate, non-covalent drug presentation clearly leads to the activation of drug-specific T cells as documented for various drugs (lidocaine, sulfamethoxazole (SMX), lamotrigine, carbamazepine, p-phenylendiamine, etc.). In some patients with drug hypersensitivity, such a response may occur within hours even upon the first exposure to the drug. Thus, the reaction to the drug may not be due to a classical, primary response, but rather be mediated by stimulating existing, pre-activated, peptide-specific T cells that are cross specific for the drug. In this way, certain drugs may circumvent the checkpoints for immune activation imposed by the classical antigen processing and presentation mechanisms, which may help to explain the peculiar nature of many drug hypersensitivity reactions.

A novel steroid-like compound F90927 exerting positive-inotropic effects in cardiac muscle

Here we report a novel steroid-like compound F90363, exhibiting positive inotropy in vivo and in vitro in various cardiac muscle preparations. F90363 is a racemic mixture composed of the stereoisomers (-)-F90926 and (+)-F90927. Only F90927 exerted positive inotropy, while F90926 induced a weak negative inotropy, but only at concentrations 10(3) times higher than F90927 and most likely resulting from an unspecific interaction. The rapid time course of the action of F90927 suggested a direct interaction with a cellular target rather than a genomic alteration. We could identify the L-type Ca2+ current I(Ca(L)) as a main target of F90927, while excluding other components of cardiac Ca2+ signalling as potential contributors. In addition, several other signaling pathways known to lead to positive inotropy (e.g. alpha- and beta-adrenergic stimulation, cAMP pathways) could be excluded as targets of F90927. However, vessel contraction and stiffening of the cardiac muscle at high doses (>30 microM, 0.36 mg kg(-1), respectively) prevent the use of F90927 as a candidate for drug development. Since the compound may still find valuable applications in research, the aim of the present study was to identify the cellular target and the mechanism of inotropy of F90927.

Cerebral formation in situ of S-carboxymethylcysteine after ifosfamide administration to mice: a further clue to the mechanism of ifosfamide encephalopathy

The clinical use of the alkylating oxazaphosphorine ifosfamide is hampered by a potentially severe encephalopathy. S-carboxymethylcysteine (SCMC), a metabolite of ifosfamide (IF), activates the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor, causes neuronal acidification, and could thus be responsible for the encephalopathy. Since the presence of SCMC in brain has not been documented following administration of IF, SCMC was measured in the brain of mice following both the individual i.p. administration of IF and SCMC. SCMC was found in a concentration of 108.2 +/- 29.7 nmol/g following IF, but was detectable at much lower levels following the administration of SCMC (21.1 +/- 21.2 nmol/g). Together with the observation that the concentration of SCMC was 10-fold higher in liver than in brain 1h after administration of SCMC, these findings suggest that the SCMC found after IF was formed in the brain in situ. The concentration of glutamic acid was similar in IF and SCMC treated animals. Methylene blue, which is used clinically to treat and to prevent IF encephalopathy, did not decrease the formation of SCMC in brain. By inhibiting monoamine oxidase activity it did, however, markedly increase the concentration of serotonin in brain which could modulate the effects of SCMC on AMPA/kainate receptors. Thus, SCMC is present in brain following the administration of IF and could contribute to the IF-associated encephalopathy by activation of AMPA/kainate receptors.

Analysis of lorazepam and its 30-glucuronide in human urine by capillary electrophoresis: evidence for the formation of two distinct diastereoisomeric glucuronides

Lorazepam (LOR) is a 3-hydroxy-1,4-benzodiazepine that is chiral and undergoes enantiomerization at room temperature. In humans, about 75% of the administered dose of LOR is excreted in the urine as its 30-glucuronide. CE-MS with negative ESI was used to confirm the presence of LOR-30-glucuronide in urines that stemmed from a healthy individual who ingested 1 or 2 mg LOR, whereas free LOR could be detected in extracts prepared from enzymatically hydrolyzed urines. As the 30-glucuronidation reaction occurs at the chiral center of the molecule, two diastereoisomers can theoretically be formed, molecules that can no longer interconvert. The stereoselective formation of LOR glucuronides in humans and in vitro was investigated. MEKC analysis of extracts of the nonhydrolyzed urines suggested the presence of the two different LOR glucuronides in the urine. The formation of the same two diastereoisomers was also observed in vitro employing incubations of LOR with human liver microsomes in the presence of uridine 5'-diphospho-glucuronic acid as coenzyme. The absence of other coenzymes excluded the formation of phase I or other phase II metabolites of LOR. Both results revealed a stereoselectivity, one diastereoisomer being formed in a higher amount than the other. After enzymatic hydrolysis using beta-glucuronidase, these peaks could not be detected any more. Instead, LOR was monitored. Analysis of the extracts prepared from enzymatically hydrolyzed urines by MEKC in the presence of 2-hydroxypropyl-beta-CD revealed the enantiomerization process of LOR (observation of two peaks of equal magnitude connected with a plateau zone). The data presented provide for the first time the evidence of the stereoselectivity of the LOR glucuronidation in humans.

Differential expression of IGF-I mRNA and peptide in the male and female gonad during early development of a bony fish, the tilapia Oreochromis niloticus

Insulin-like growth factor I (IGF-I) plays a key role in the complex system that regulates bony fish growth, differentiation, and reproduction. The major source of circulating IGF-I is liver, but IGF-I-producing cells also occur in other organs, including the gonads. Because no data are available on the potential production sites of IGF-I in gonad development, developmental stages of monosex breedings of male and female tilapia from 0 day postfertilization (DPF) to 90 DPF were investigated for the production sites of IGF-I at the peptide (immunohistochemistry) and mRNA (in situ hybridization) level. IGF-I mRNA first appeared in somatic cells of the male and female gonad anlage at 7 DPF followed by IGF-I peptide around 9-10 DPF. Gonad anlagen were detected from 7 DPF. Starting at 7 DPF, IGF-I peptide but no IGF-I mRNA was observed in male and female primordial germ cells (PGCs) provided that IGF-I mRNA was not under the detection level, this observation may suggest that IGF-I originates from the somatic cells and is transferred to the PGCs or is of maternal origin. While in female germ cells IGF-I mRNA and peptide appeared at 29 DPF, in male germ cells both were detected as late as at 51-53 DPF. It is assumed that the production of IGF-I in the germ cells is linked to the onset of meiosis that in tilapia ovary starts at around 28 DPF and in testes at around 52-53 DPF. In adult testis, IGF-I mRNA and peptide occurred in the majority of spermatogonia and spermatocytes as well as in Leydig cells, the latter indicating a role of IGF-I in the synthesis of male sex steroids. In adult ovary, IGF-I mRNA and IGF-I peptide were always present in small and previtellogenic oocytes but only IGF-I peptide infrequently occurred in oocytes at the later stages. IGF-I expression appeared in numerous granulosa and some theca cells of follicles at the lipid stage and persisted in follicles with mature oocytes. The results suggest a crucial role of local IGF-I in the formation, differentiation and function of tilapia gonads.

Cyclooxygenase-2 inhibition selectively attenuates bone morphogenetic protein-6 synthesis and bone formation during guided tissue regeneration in a rat model

OBJECTIVES: Bone formation during guided tissue regeneration is a tightly regulated process involving cells, extracellular matrix and growth factors. The aims of this study were (i) to examine the expression of cyclooxygenase-2 (COX-2) during bone regeneration and (ii) the effects of selective COX-2 inhibition on osseous regeneration and growth factor expression in the rodent femur model. MATERIAL AND METHODS: A standardized transcortical defect of 5 x 1.5 mm was prepared in the femur of 12 male rats and a closed half-cylindrical titanium chamber was placed over the defect. The expression of COX-2 and of platelet-derived growth factor-B (PDGF-B), bone morphogenetic protein-6 (BMP-6) and insulin-like growth factor-I/II (IGF-I/II) was analyzed at Days 3, 7, 21 and 28 semiquantitatively by reverse transcriptase-polymerase chain reaction and immunohistochemistry. The effects of COX-2 inhibition by intraperitoneal injection of NS-398 (3 mg/kg/day) were analyzed in five additional animals sacrificed at Day 14. RESULTS: Histomorphometry revealed that new bone formation occurred in the cortical defect area as well as in the supracortical region, i.e. region within the chamber by Day 7 and increased through Day 28. Immunohistochemical evidence of COX-2 and PDGF-B levels were observed early (i.e. Day 3) and decreased rapidly by Day 7. BMP-6 expression was maximal at Day 3 and slowly declined by Day 28. In contrast, IGF-I/II expression gradually increased during the 28-day period. Systemic administration NS-398 caused a statistically significant reduction (P<0.05) in new bone formation (25-30%) and was associated with a statistically significant reduction in BMP-6 protein and mRNA expression (50% and 65% at P<0.05 and P<0.01, respectively). PDGF-B mRNA or protein expression was not affected by NS-398 treatment. CONCLUSION: COX-2 inhibition resulted in reduced BMP-6 expression and impaired osseous regeneration suggesting an important role for COX-2-induced signaling in BMP synthesis and new bone formation.

Homozygous Cys542-->Arg substitution in GPIIIa in a Swiss patient with type I Glanzmann's thrombasthenia

Glanzmann's thrombasthenia (GT) arises from a qualitative or quantitative defect in the GPIIb-IIIa complex (integrin alphaIIbbeta3), the mediator of platelet aggregation. We describe a patient in whom clinical and laboratory findings typical of type I GT were found together with a second pathology involving neurological and other complications symptomatic of tuberous sclerosis. Analysis of platelet proteins by Western blotting revealed trace amounts of normally migrating GPIIb and equally small amounts of GPIIIa of slightly slower than normal migration. Flow cytometry confirmed a much decreased binding to platelets of monoclonal antibodies to GPIIb, GPIIIa or GPIIb-IIIa, and an antibody to the alphav subunit also showed decreased binding. Nonradioactive PCR single-strand conformation polymorphism analysis followed by direct sequencing of PCR-amplified DNA fragments showed a homozygous point mutation (T to C) at nucleotide 1722 of GPIIIa cDNA and which led to a Cys542-->Arg substitution in the GPIIIa protein. The mutation gave rise to a HinP1 I restriction site in exon 11 of the GPIIIa gene and allele-specific restriction enzyme analysis of family members confirmed that a single mutated allele was inherited from each parent. This amino acid substitution presumably changes the capacity for disulphide bond formation within the cysteine-rich core region of GPIIIa and its study will provide new information on GPIIb-IIIa and alphavbeta3 structure and biosynthesis.

Impact of preservation solution on the extent of blood-air barrier damage and edema formation in experimental lung transplantation

A major aim in lung transplantation is to prevent the loss of structural integrity due to ischemia and reperfusion (I/R) injury. Preservation solutions protect the lung against I/R injury to a variable extent. We compared the influence of two extracellular-type preservation solutions (Perfadex, or PX, and Celsior, or CE) on the morphological alterations induced by I/R. Pigs were randomly assigned to sham (n = 4), PX (n = 5), or CE (n = 2) group. After flush perfusion with PX or CE, donor lungs were excised and stored for 27 hr at 4 degrees C. The left donor lung was implanted into the recipient, reperfused for 6 hr, and, afterward, prepared for light and electron microscopy. Intra-alveolar, septal, and peribronchovascular edema as well as the integrity of the blood-air barrier were determined stereologically. Intra-alveolar edema was more pronounced in CE (219.80 +/- 207.55 ml) than in PX (31.46 +/- 15.75 ml). Peribronchovascular (sham: 13.20 +/- 4.99 ml; PX: 15.57 +/- 5.53 ml; CE: 31.56 +/- 5.78 ml) and septal edema (thickness of alveolar septal interstitium, sham: 98 +/- 33 nm; PX: 84 +/- 8 nm; CE: 249 +/- 85 nm) were only found in CE. The blood-air barrier was similarly well preserved in sham and PX but showed larger areas of swollen and fragmented epithelium or endothelium in CE. The present study shows that Perfadex effectively prevents intra-alveolar, septal, and peribronchovascular edema formation as well as injury of the blood-air barrier during I/R. Celsior was not effective in preserving the lung from morphological I/R injury.

Infantile hypophosphatasia due to a new compound heterozygous TNSALP mutation - functional evidence for a hydrophobic side-chain?

BACKGROUND: Infantile hypophosphatasia (IH) is an inherited disorder characterized by defective bone mineralization and a deficiency of alkaline phosphatase activity. OBJECTIVE/DESIGN: The aim of the study was to evaluate a new compound heterozygous TNSALP mutation for its residual enzyme activity and localization of the comprised amino acid residues in a 3D-modeling. PATIENT: We report on a 4-week old girl with craniotabes, severe defects of ossification, and failure to thrive. Typical clinical features as low serum alkaline phosphatase, high serum calcium concentration, increased urinary calcium excretion, and nephrocalcinosis were observed. Vitamin D was withdrawn and the patient was started on calcitonin and hydrochlorothiazide. Nonetheless, the girl died at the age of 5 months from respiratory failure. RESULTS: Sequence analysis of the patient's TNSALP gene revealed two heterozygous mutations [c.653T>C (I201T), c.1171C>T (R374C)]. Transfection studies of the unique I201T variant in COS-7 cells yielded a mutant TNSALP protein with only a residual enzyme activity (3.7%) compared with wild-type, whereas the R374C variant was previously shown to reduce normal activity to 10.3%. 3D-modeling of the mutated enzyme showed that I201T resides in a region that does not belong to any known functional site. CONCLUSION: We note that I201, which has been conserved during evolution, is buried in a hydrophobic pocket and, therefore, the I>T-change should affect its functional properties. Residue R374C is located in the interface between monomers and it has been previously suggested that this mutation affects dimerization. These findings explain the patient's clinical picture and severe course.

Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation

The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a (45)Ca(2+) uptake assay (7.11 +/- 1.93 versus 3.61 +/- 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuria.

In-situ electrical, mechanical and electrochemical characterizations of one-dimensional nanostructures

One-dimensional nanostructures initiated new aspects to the materials applications due to their superior properties compared to the bulk materials. Properties of nanostructures have been characterized by many techniques and used for various device applications. However, simultaneous correlation between the physical and structural properties of these nanomaterials has not been widely investigated. Therefore, it is necessary to perform in-situ study on the physical and structural properties of nanomaterials to understand their relation. In this work, we will use a unique instrument to perform real time atomic force microscopy (AFM) and scanning tunneling microscopy (STM) of nanomaterials inside a transmission electron microscopy (TEM) system. This AFM/STM-TEM system is used to investigate the mechanical, electrical, and electrochemical properties of boron nitride nanotubes (BNNTs) and Silicon nanorods (SiNRs). BNNTs are one of the subjects of this PhD research due to their comparable, and in some cases superior, properties compared to carbon nanotubes. Therefore, to further develop their applications, it is required to investigate these characteristics in atomic level. In this research, the mechanical properties of multi-walled BNNTs were first studied. Several tests were designed to study and characterize their real-time deformation behavior to the applied force. Observations revealed that BNNTs possess highly flexible structures under applied force. Detailed studies were then conducted to understand the bending mechanism of the BNNTs. Formations of reversible ripples were observed and described in terms of thermodynamic energy of the system. Fracture failure of BNNTs were initiated at the outermost walls and characterized to be brittle. Second, the electrical properties of individual BNNTs were studied. Results showed that the bandgap and electronic properties of BNNTs can be engineered by means of applied strain. It was found that the conductivity, electron concentration and carrier mobility of BNNTs can be tuned as a function of applied stress. Although, BNNTs are considered to be candidate for field emission applications, observations revealed that their properties degrade upon cycles of emissions. Results showed that due to the high emission current density, the temperature of the sample was increased and reached to the decomposition temperature at which the B-N bonds start to break. In addition to BNNTs, we have also performed in-situ study on the electrochemical properties of silicon nanorods (SiNRs). Specifically, lithiation and delithiation of SiNRs were studied by our STM-TEM system. Our observations showed the direct formation of Li22Si5 phases as a result of lithium intercalation. Radial expansion of the anode materials were observed and characterized in terms of size-scale. Later, the formation and growth of the lithium fibers on the surface of the anode materials were observed and studied. Results revealed the formation of lithium islands inside the ionic liquid electrolyte which then grew as Li dendrite toward the cathode material.

Interrogating the spaces of personal photography : women, identity, and the cultural formation of photographic practice

Personal photographs permeate our lives from the moment we are born as they define who we are within our familial group and local communities. Archived in family albums or framed on living room walls, they continue on after our death as mnemonic artifacts referencing our gendered, raced, and ethnic identities. This dissertation examines salient instances of what women “do” with personal photographs, not only as authors and subjects but also as collectors, archivists, and family and cultural historians. This project seeks to contribute to more productive, complex discourse about how women form relationships and engage with the conventions and practices of personal photography. In the first part of this dissertation I revisit developments in the history of personal photography, including the advertising campaigns of the Kodak and Agfa Girls and the development of albums such as the Stammbuch and its predecessor, the carte-de-visite, that demonstrate how personal photography has functioned as a gendered activity that references family unity, sentimentalism for the past, and self-representation within normative familial and dominant cultural groups, thus suggesting its importance as a cultural practice of identity formation. The second and primary section of the dissertation expands on the critical analyses of Gillian Rose, Patricia Holland, and Nancy Martha West, who propose that personal photography, marketed to and taken on by women, double-exposes their gendered identities. Drawing on work by critics such as Deborah Willis, bell hooks, and Abigail Solomon-Godeau, I examine how the reconfiguration, recontextualization, and relocation of personal photographs in the respective work of Christine Saari, Fern Logan, and Katie Knight interrogates and complicates gendered, raced, and ethnic identities and cultural attitudes about them. In the final section of the dissertation I briefly examine select examples of how emerging digital spaces on the Internet function as a site for personal photography, one that both reinscribes traditional cultural formations while offering new opportunities for women for the display and audiencing of identities outside the family.

Uptake and fate of hexahydro-1,3,5-trinitro-1,3,5-triazine by Chrysopogon zizanioides

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a nitramine compound that has been used heavily by the military as an explosive. Manufacturing, use, and disposal of RDX have led to several contamination sites across the United States. RDX is both persistent in the environment and a threat to human health, making its remediation vital. The use of plants to extract RDX from the soil and metabolize it once it is in the plant tissue, is being considered as a possible solution. In the present study, the tropical grass Chrysopogon zizanioides was grown hydroponically in the presence RDX at 3 different concentration levels: 0.3, 1.1, and 2.26 ppm. The uptake of RDX was quantified by high performance liquid chromatography (HPLC) analysis of media samples taken every 6 hr during the first 24 hr and then daily over a 30-day experimental period. A rapid decrease in RDX concentration in the media of both controls and plant treatments was seen within the first 18 hours of the experiment with the greatest loss in RDX over time occurring within the first 6 hours of exposure. The loss was similar in both controls and plant exposures and possibly attributed to rapid uptake by the containers. A plant from one treatment at each of the three concentrations was harvested at Day 10, 20 and 30 throughout the experiment and extracted to determine the localization of RDX within the tissue and potentially identify any metabolites on the basis of differing retention times. Of the treatments containing 0.3, 1.1, and 2.26 ppm RDX, 13.1%, 18.3%, and 24.2% respectively, was quantified in vetiver extracts, with the majority of the RDX being localized to the roots. All plants not yet harvested were harvested on Day 30 of the experiment. A total of three plants exposed to each concentration level as well as the control, were extracted and analyzed with HPLC to determine amount of RDX taken up, localization of RDX within the plant tissue, and potentially identify any metabolites. Phytotoxicity of RDX to vetiver was also monitored. While a loss in biomass was observed in plants exposed to all the different concentrations of RDX, control plants grown in media not exposed to RDX showed the greatest biomass loss of all the treatments. There was also little variation in chlorophyll content between the different concentration treatments with RDX. This preliminary greenhouse study of RDX uptake 10 by Chrysopogon zizanioides will help indicate the potential ability of vetiver to serve as a plant system in the phytoremediation of RDX.

Exogenous surfactant application in a rat lung ischemia reperfusion injury model: effects on edema formation and alveolar type II cells

BACKGROUND: Prophylactic exogenous surfactant therapy is a promising way to attenuate the ischemia and reperfusion (I/R) injury associated with lung transplantation and thereby to decrease the clinical occurrence of acute lung injury and acute respiratory distress syndrome. However, there is little information on the mode by which exogenous surfactant attenuates I/R injury of the lung. We hypothesized that exogenous surfactant may act by limiting pulmonary edema formation and by enhancing alveolar type II cell and lamellar body preservation. Therefore, we investigated the effect of exogenous surfactant therapy on the formation of pulmonary edema in different lung compartments and on the ultrastructure of the surfactant producing alveolar epithelial type II cells. METHODS: Rats were randomly assigned to a control, Celsior (CE) or Celsior + surfactant (CE+S) group (n = 5 each). In both Celsior groups, the lungs were flush-perfused with Celsior and subsequently exposed to 4 h of extracorporeal ischemia at 4 degrees C and 50 min of reperfusion at 37 degrees C. The CE+S group received an intratracheal bolus of a modified natural bovine surfactant at a dosage of 50 mg/kg body weight before flush perfusion. After reperfusion (Celsior groups) or immediately after sacrifice (Control), the lungs were fixed by vascular perfusion and processed for light and electron microscopy. Stereology was used to quantify edematous changes as well as alterations of the alveolar epithelial type II cells. RESULTS: Surfactant treatment decreased the intraalveolar edema formation (mean (coefficient of variation): CE: 160 mm3 (0.61) vs. CE+S: 4 mm3 (0.75); p < 0.05) and the development of atelectases (CE: 342 mm3 (0.90) vs. CE+S: 0 mm3; p < 0.05) but led to a higher degree of peribronchovascular edema (CE: 89 mm3 (0.39) vs. CE+S: 268 mm3 (0.43); p < 0.05). Alveolar type II cells were similarly swollen in CE (423 microm3(0.10)) and CE+S (481 microm3(0.10)) compared with controls (323 microm3(0.07); p < 0.05 vs. CE and CE+S). The number of lamellar bodies was increased and the mean lamellar body volume was decreased in both CE groups compared with the control group (p < 0.05). CONCLUSION: Intratracheal surfactant application before I/R significantly reduces the intraalveolar edema formation and development of atelectases but leads to an increased development of peribronchovascular edema. Morphological changes of alveolar type II cells due to I/R are not affected by surfactant treatment. The beneficial effects of exogenous surfactant therapy are related to the intraalveolar activity of the exogenous surfactant.

Modulating the granularity of category formation by global cortical states

The unsupervised categorization of sensory stimuli is typically attributed to feedforward processing in a hierarchy of cortical areas. This purely sensory-driven view of cortical processing, however, ignores any internal modulation, e.g., by top-down attentional signals or neuromodulator release. To isolate the role of internal signaling on category formation, we consider an unbroken continuum of stimuli without intrinsic category boundaries. We show that a competitive network, shaped by recurrent inhibition and endowed with Hebbian and homeostatic synaptic plasticity, can enforce stimulus categorization. The degree of competition is internally controlled by the neuronal gain and the strength of inhibition. Strong competition leads to the formation of many attracting network states, each being evoked by a distinct subset of stimuli and representing a category. Weak competition allows more neurons to be co-active, resulting in fewer but larger categories. We conclude that the granularity of cortical category formation, i.e., the number and size of emerging categories, is not simply determined by the richness of the stimulus environment, but rather by some global internal signal modulating the network dynamics. The model also explains the salient non-additivity of visual object representation observed in the monkey inferotemporal (IT) cortex. Furthermore, it offers an explanation of a previously observed, demand-dependent modulation of IT activity on a stimulus categorization task and of categorization-related cognitive deficits in schizophrenic patients.