Classification of acute appendicitis (CAA): treatment directed new classification based on imaging (ultrasound, computed tomography) and pathology.

PURPOSE: Acute appendicitis (AA) is amongst the most common causes of acute abdominal pain. In spite of progress based on risk stratifications, "negative" appendectomies are performed in up to 30% of patients whilst the appendix perforates in others. Preoperative classification of AA based on imaging is therefore recommended. The aim was to classify AA based on imaging (ultrasound/US, computed tomography/CT), surgical pathology, and/or histopathology in order to differentiate between complicated and uncomplicated AA. A new classification of acute appendicitis (CAA) shall be illustrated by typical US and CT images and be employed in a diagnostic and therapeutic algorithm. METHODS: Medline, Embase, and the Cochrane Library were searched. Any study after 1970, which investigated clinical scores, pathology, US, CT, magnetic resonance imaging, and treatment of AA, was included. Typical images were taken from the author's image database. RESULTS: Five main types of AA are defined, normal appendix (type 0), nonvisualised appendix (type X), uncomplicated AA (type 1), complicated AA without perforation (type 2), and complicated AA with perforation (type 3). The imaging modality is indicated by an additional letter, e.g., type p3b for free perforation on pathology. Standardised reporting of the appendix evaluation by US and CT is presented, as well as algorithms for AA management. Imaging features indicating imminent perforation, as well as likely recurrence, were both classified as complicated AA. CONCLUSION: Imaging is mandatory in suspected AA. The CAA clearly separates uncomplicated from complicated forms of AA allowing nonoperative management in selected patients with uncomplicated forms of AA.

Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation.

Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT2 receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients.

Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma.

Obstructive lung diseases are common causes of disability and death worldwide. A hallmark feature is aberrant activation of Gq protein-dependent signaling cascades. Currently, drugs targeting single G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) are used to reduce airway tone. However, therapeutic efficacy is often limited, because various GPCRs contribute to bronchoconstriction, and chronic exposure to receptor-activating medications results in desensitization. We therefore hypothesized that pharmacological Gq inhibition could serve as a central mechanism to achieve efficient therapeutic bronchorelaxation. We found that the compound FR900359 (FR), a membrane-permeable inhibitor of Gq, was effective in silencing Gq signaling in murine and human airway smooth muscle cells. Moreover, FR both prevented bronchoconstrictor responses and triggered sustained airway relaxation in mouse, pig, and human airway tissue ex vivo. Inhalation of FR in healthy wild-type mice resulted in high local concentrations of the compound in the lungs and prevented airway constriction without acute effects on blood pressure and heart rate. FR administration also protected against airway hyperreactivity in murine models of allergen sensitization using ovalbumin and house dust mite as allergens. Our findings establish FR as a selective Gq inhibitor when applied locally to the airways of mice in vivo and suggest that pharmacological blockade of Gq proteins may be a useful therapeutic strategy to achieve bronchorelaxation in asthmatic lung disease.

The Orphan Receptor GPR17 Is Unresponsive to Uracil Nucleotides and Cysteinyl Leukotrienes.

Pairing orphan G protein­coupled receptors (GPCRs) with their cognate endogenous ligands is expected to have a major impact on our understanding of GPCR biology. It follows that the reproducibility of orphan receptor ligand pairs should be of fundamental importance to guide meaningful investigations into the pharmacology and function of individual receptors. GPR17 is an orphan receptor characterized by some as a dualistic uracil nucleotide/cysteinyl leukotriene receptor and by others as inactive toward these stimuli altogether. Whereas regulation of central nervous system myelination by GPR17 is well established, verification of activity of its putative endogenous ligands has proven elusive so far. Herein we report that uracil nucleotides and cysteinyl leukotrienes do not activate human, mouse, or rat GPR17 in various cellular backgrounds, including primary cells, using eight distinct functional assay platforms based on labelfree pathway-unbiased biosensor technologies, as well as canonical second-messenger or biochemical assays. Appraisal of GPR17 activity can neither be accomplished with co-application of both ligand classes, nor with exogenous transfection of partner receptors (nucleotide P2Y12, cysteinyl-leukotriene CysLT1) to reconstitute the elusive pharmacology. Moreover, our study does not support the inhibition of GPR17 by the marketed antiplatelet drugs cangrelor and ticagrelor, previously suggested to antagonize GPR17. Whereas our data do not disagree with a role of GPR17 per se as an orchestrator of central nervous system functions, they challenge the utility of the proposed (ant)agonists as tools to imply direct contribution of GPR17 in complex biologic settings.

A cell-permeable inhibitor to trap Gαq proteins in the empty pocket conformation.

In spite of the crucial role of heterotrimeric G proteins as molecular switches transmitting signals from G protein-coupled receptors, their selective manipulation with small molecule, cell-permeable inhibitors still remains an unmet challenge. Here, we report that the small molecule BIM-46187, previously classified as pan-G protein inhibitor, preferentially silences Gαq signaling in a cellular context-dependent manner. Investigations into its mode of action reveal that BIM traps Gαq in the empty pocket conformation by permitting GDP exit but interdicting GTP entry, a molecular mechanism not yet assigned to any other small molecule Gα inhibitor to date. Our data show that Gα proteins may be "frozen" pharmacologically in an intermediate conformation along their activation pathway and propose a pharmacological strategy to specifically silence Gα subclasses with cell-permeable inhibitors.

ß-arrestin 2 inhibits proinflammatory chemokine production and attenuates contact allergic inflammation in the skin.

ß-Arrestins participate in G-protein receptor signaling and act as adapter proteins that direct the recruitment, activation, and scaffolding of various cytoplasmic signaling complexes. ß-Arrestin 2-deficient (Arrb2(-/-)) mice show decreased T-cell recruitment into allergic lung tissue but increased neutrophil infiltration into wounded skin. Given these opposing effects in different immune cell subsets, we investigated the role of ß-arrestin 2 in the regulation of contact hypersensitivity responses. We observed significantly increased allergic ear swelling to the obligate contact sensitizers DNFB and FITC in Arrb2(-/-) compared with wild-type mice. Immunohistological analyses revealed strikingly increased neutrophil infiltration with abundant subcorneal pustules in inflamed ear tissue of DNFB-allergic Arrb2(-/-) mice. Experiments involving adoptive transfers of sensitized lymphocytes and bone marrow chimeric mice indicated that ß-arrestin 2 exerts its anti-inflammatory effects predominantly through radioresistant, skin-resident cells in the challenge phase of contact hypersensitivity. As a potential mechanism, we found that primary cultures of ß-arrestin 2-deficient keratinocytes secreted higher levels of neutrophil-attracting chemokines including CXCL1/KC in response to T cell-derived cytokines in vitro. These experimental results support a model in which ß-arrestin 2 inhibits the production of proinflammatory chemokines, which limits the recruitment of myeloid immune cells and thereby attenuates allergic skin inflammation.

Decoding signaling and function of the orphan G protein-coupled receptor GPR17 with a small-molecule agonist.

Replacement of the lost myelin sheath is a therapeutic goal for treating demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS). The G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR17, which is phylogenetically closely related to receptors of the "purinergic cluster," has emerged as a modulator of CNS myelination. However, whether GPR17-mediated signaling positively or negatively regulates this critical process is unresolved. We identified a small-molecule agonist, MDL29,951, that selectively activated GPR17 even in a complex environment of endogenous purinergic receptors in primary oligodendrocytes. MDL29,951-stimulated GPR17 engaged the entire set of intracellular adaptor proteins for GPCRs: G proteins of the Gα(i), Gα(s), and Gα(q) subfamily, as well as ß-arrestins. This was visualized as alterations in the concentrations of cyclic adenosine monophosphate and inositol phosphate, increased Ca²âº flux, phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), as well as multifeatured cell activation recorded with label-free dynamic mass redistribution and impedance biosensors. MDL29,951 inhibited the maturation of primary oligodendrocytes from heterozygous but not GPR17 knockout mice in culture, as well as in cerebellar slices from 4-day-old wild-type mice. Because GPCRs are attractive targets for therapeutic intervention, inhibiting GPR17 emerges as therapeutic strategy to relieve the oligodendrocyte maturation block and promote myelin repair in MS.

Free fatty acid receptor 1 (FFA1/GPR40) agonists: mesylpropoxy appendage lowers lipophilicity and improves ADME properties.

FFA1 (GPR40) is a new target for treatment of type 2 diabetes. We recently identified the potent FFA1 agonist TUG-469 (5). Inspired by the structurally related TAK-875, we explored the effects of a mesylpropoxy appendage on 5. The appendage significantly lowers lipophilicity and improves metabolic stability while preserving potency, resulting in discovery of the potent FFA1 agonist 13.

A biased ligand for OXE-R uncouples Gα and Gßγ signaling within a heterotrimer.

Differential targeting of heterotrimeric G protein versus ß-arrestin signaling are emerging concepts in G protein-coupled receptor (GPCR) research and drug discovery, and biased engagement by GPCR ligands of either ß-arrestin or G protein pathways has been disclosed. Herein we report on a new mechanism of ligand bias to titrate the signaling specificity of a cell-surface GPCR. Using a combination of biomolecular and virtual screening, we identified the small-molecule modulator Gue1654, which inhibits Gßγ but not Gα signaling triggered upon activation of Gα(i)-ßγ by the chemoattractant receptor OXE-R in both recombinant and human primary cells. Gue1654 does not interfere nonspecifically with signaling directly at or downstream of Gßγ. This hitherto unappreciated mechanism of ligand bias at a GPCR highlights both a new paradigm for functional selectivity and a potentially new strategy to develop pathway-specific therapeutics.

PGH1, the precursor for the anti-inflammatory prostaglandins of the 1-series, is a potent activator of the pro-inflammatory receptor CRTH2/DP2.

Prostaglandin H(1) (PGH(1)) is the cyclo-oxygenase metabolite of dihomo-γ-linolenic acid (DGLA) and the precursor for the 1-series of prostaglandins which are often viewed as "anti-inflammatory". Herein we present evidence that PGH(1) is a potent activator of the pro-inflammatory PGD(2) receptor CRTH2, an attractive therapeutic target to treat allergic diseases such as asthma and atopic dermatitis. Non-invasive, real time dynamic mass redistribution analysis of living human CRTH2 transfectants and Ca(2+) flux studies reveal that PGH(1) activates CRTH2 as PGH(2), PGD(2) or PGD(1) do. The PGH(1) precursor DGLA and the other PGH(1) metabolites did not display such effect. PGH(1) specifically internalizes CRTH2 in stable CRTH2 transfectants as assessed by antibody feeding assays. Physiological relevance of CRTH2 ligation by PGH(1) is demonstrated in several primary human hematopoietic lineages, which endogenously express CRTH2: PGH(1) mediates migration of and Ca(2+) flux in Th2 lymphocytes, shape change of eosinophils, and their adhesion to human pulmonary microvascular endothelial cells under physiological flow conditions. All these effects are abrogated in the presence of the CRTH2 specific antagonist TM30089. Together, our results identify PGH(1) as an important lipid intermediate and novel CRTH2 agonist which may trigger CRTH2 activation in vivo in the absence of functional prostaglandin D synthase.

D-type prostanoid receptor enhances the signaling of chemoattractant receptor-homologous molecule expressed on T(H)2 cells.

BACKGROUND: Prostaglandin (PG) D(2) is substantially involved in allergic responses and signals through the 7 transmembrane-spanning/G protein-coupled receptors, chemoattractant receptor-homologous molecule expressed on T(H)2 cells (CRTH2), and D-type prostanoid (DP) receptor. OBJECTIVE: Although the proinflammatory function of CRTH2 is well recognized and CRTH2 is hence considered an important emerging pharmacotherapeutic target, the role of the DP receptor in mediating the biological effects of PGD(2) in patients with allergic inflammation has remained unclear. METHODS: The cross-talk of CRTH2 and DP receptors was investigated by using both a recombinant HEK293 cell model and human eosinophils in Ca(2+) mobilization assays, coimmunoprecipitation, Western blotting, radioligand binding, and immunofluorescence. RESULTS: We show that CRTH2 and DP receptors modulate one another's signaling properties and form CRTH2/DP heteromers without altering their ligand-binding capacities. We find that the DP receptor amplifies the CRTH2-induced Ca(2+) release from intracellular stores and coincidentally forfeits its own signaling potency. Moreover, desensitization or pharmacologic blockade of the DP receptor hinders CRTH2-mediated signal transduction. However, CRTH2 internalization occurs independently of the DP receptor. In cells that express both receptors, pharmacologic blockade of Gα(q/11) proteins abolishes the Ca(2+) response to both CRTH2 and DP agonists, whereas inhibition of Gα(i) proteins selectively attenuates the CRTH2-mediated response but not the DP signal. CONCLUSION: Our data demonstrate the capacity of DP receptors to amplify the biological response to CRTH2 activation. Therefore the CRTH2/DP heteromer might not only represent a functional signaling unit for PGD(2) but also a potential target for the development of heteromer-directed therapies to treat allergic diseases.

Applying label-free dynamic mass redistribution technology to frame signaling of G protein-coupled receptors noninvasively in living cells.

Label-free dynamic mass redistribution (DMR) is a cutting-edge assay technology that enables real-time detection of integrated cellular responses in living cells. It relies on detection of refractive index alterations on biosensor-coated microplates that originate from stimulus-induced changes in the total biomass proximal to the sensor surface. Here we describe a detailed protocol to apply DMR technology to frame functional behavior of G protein-coupled receptors that are traditionally examined with end point assays on the basis of detection of individual second messengers, such as cAMP, Ca(2+) or inositol phosphates. The method can be readily adapted across diverse cellular backgrounds (adherent or suspension), including primary human cells. Real-time recordings can be performed in 384-well microtiter plates and be completed in 2 h, or they can be extended to several hours depending on the biological question to be addressed. The entire procedure, including cell harvesting and DMR detection, takes 1-2 d.

GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils.

The directional migration of neutrophils towards inflammatory mediators, such as chemokines and cannabinoids, occurs via the activation of seven transmembrane G protein coupled receptors (7TM/GPCRs) and is a highly organized process. A crucial role for controlling neutrophil migration has been ascribed to the cannabinoid CB(2) receptor (CB(2)R), but additional modulatory sites distinct from CB(2)R have recently been suggested to impact CB(2)R-mediated effector functions in neutrophils. Here, we provide evidence that the recently de-orphanized 7TM/GPCR GPR55 potently modulates CB(2)R-mediated responses. We show that GPR55 is expressed in human blood neutrophils and its activation augments the migratory response towards the CB(2)R agonist 2-arachidonoylglycerol (2-AG), while inhibiting neutrophil degranulation and reactive oxygen species (ROS) production. Using HEK293 and HL60 cell lines, along with primary neutrophils, we show that GPR55 and CB(2)R interfere with each other's signaling pathways at the level of small GTPases, such as Rac2 and Cdc42. This ultimately leads to cellular polarization and efficient migration as well as abrogation of degranulation and ROS formation in neutrophils. Therefore, GPR55 limits the tissue-injuring inflammatory responses mediated by CB(2)R, while it synergizes with CB(2)R in recruiting neutrophils to sites of inflammation.

Arthroscopic soft tissue tenodesis versus bony fixation anchor tenodesis of the long head of the biceps tendon.

BACKGROUND: Currently there are no prospective data available that compare the different tenodesis techniques of the long head of the biceps tendon with regard to their clinical and structural results. HYPOTHESIS: Soft tissue tenodesis provides clinical and structural results equivalent to those of bony fixation anchor tenodesis. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Fifty-seven patients with arthroscopically proven lesions of the long head of the biceps tendon (LHB) were prospectively included in this study. Thirty patients (7 women, 23 men; mean age, 57.9 years) were treated with an arthroscopic soft tissue tenodesis (STT) and 27 patients (8 women, 19 men; mean age, 61 years) with an arthroscopic bony fixation anchor tenodesis (BFAT). The clinical evaluation included the Constant score as well as a newly developed LHB score (maximum 100 points) that includes evaluation of pain and cramps (maximum 50 points), the patient- and examiner-dependent grading of the cosmetic result (maximum 30 points), and the measurement of elbow flexion strength (maximum 20 points). The integrity of the tenodesis construct was evaluated indirectly by detecting the position of the LHB using magnetic resonance imaging. A proximal intertubercular location of the tendon was judged as an intact tenodesis construct (3 points), a distal intertubercular location as a failure of tenodesis followed by autotenodesis in the sulcus (2 points), and an extratubercular location as a complete failure (1 point). RESULTS: Twenty-four patients (5 women, 19 men; mean age, 58.6 years; mean follow-up, 19.6 months) in the STT group and 20 patients (5 women, 15 men; mean age, 59.1 years; mean follow-up, 22.4 months) in the BFAT group could be evaluated. The overall Constant score did not reveal any significant difference in the STT group (mean, 75.0 points) compared with the BFAT group (mean, 78.3 points) (P > .05). However, the BFAT group showed significantly better results in the LHB score (BFAT mean, 91.8 points vs STT mean, 80.9 points), the examiner-dependent evaluation of the cosmetic result (BFAT mean, 11.3 points vs STT mean, 8.0 points), as well as in the evaluation of the structural integrity of the tenodesis construct (BFAT mean, 2.7 points vs STT mean, 2.2 points) (P < .05). CONCLUSION: When arthroscopic tenodesis of the LHB is indicated, the authors recommend a bony fixation over soft tissue fixation because anchor fixation provides significant advantages concerning the clinical and structural outcome.

Deconvolution of complex G protein-coupled receptor signaling in live cells using dynamic mass redistribution measurements.

Label-free biosensor technology based on dynamic mass redistribution (DMR) of cellular constituents promises to translate GPCR signaling into complex optical 'fingerprints' in real time in living cells. Here we present a strategy to map cellular mechanisms that define label-free responses, and we compare DMR technology with traditional second-messenger assays that are currently the state of the art in GPCR drug discovery. The holistic nature of DMR measurements enabled us to (i) probe GPCR functionality along all four G-protein signaling pathways, something presently beyond reach of most other assay platforms; (ii) dissect complex GPCR signaling patterns even in primary human cells with unprecedented accuracy; (iii) define heterotrimeric G proteins as triggers for the complex optical fingerprints; and (iv) disclose previously undetected features of GPCR behavior. Our results suggest that DMR technology will have a substantial impact on systems biology and systems pharmacology as well as for the discovery of drugs with novel mechanisms.

GPR55 ligands promote receptor coupling to multiple signalling pathways.

BACKGROUND AND PURPOSE: Although GPR55 is potently activated by the endogenous lysophospholipid, L-alpha-lysophosphatidylinositol (LPI), it is also thought to be sensitive to a number of cannabinoid ligands, including the prototypic CB1 receptor antagonists AM251 and SR141716A (Rimonabant). In this study we have used a range of functional assays to compare the pharmacological activity of selected cannabinoid ligands, AM251, AM281 and SR141716A with LPI in a HEK293 cell line engineered to stably express recombinant, human GPR55. EXPERIMENTAL APPROACH: We evaluated Ca(2+) signalling, stimulation of extracellular signal regulated kinase (ERK1/2) mitogen activated kinase MAP-kinases, induction of transcriptional regulators that are downstream of GPR55, including nuclear factor of activated T cells (NFAT), nuclear factor-kappaB (NF-kappaB) and cAMP response element binding protein (CREB), as well as receptor endocytosis. In addition, we assessed the suitability of a novel, label-free assay for GPR55 ligands that involves optical measurement of dynamic mass redistribution following receptor activation. KEY RESULTS: GPR55 linked to a range of downstream signalling events and that the activity of GPR55 ligands was influenced by the functional assay employed, with differences in potency and efficacy observed. CONCLUSIONS AND IMPLICATIONS: Our data help to resolve some of the issues surrounding the pharmacology of cannabinoid ligands at GPR55 and highlight some differences in effector coupling associated with distinct GPR55 ligands.

Biphasic blood pool contrast agent-enhanced whole-body MR angiography for treatment planning in patients with significant arterial stenosis.

OBJECTIVE: To prospectively evaluate diagnostic accuracy of first pass and combined first pass and steady state high-spatial-resolution whole-body magnetic resonance (MR) angiography with a blood pool contrast agent for quantification of arterial stenosis in different vascular territories. MATERIALS AND METHODS: After Institutional Review Board approval and informed consent, 50 patients with known 50% or greater stenosis in at least one vascular territory; as shown by the standard-of-reference (14 digital subtraction angiographies, 4 computed tomographies, 32 ultrasound examinations), were included. The patients underwent MR angiography at 1.5 Tesla, using a standardized nonbody-weight-adapted i.v. bolus injection of 11 mL gadofosveset trisodium. First pass imaging with 4 different table positions in a whole-body MR scanner (MAGNETOM Avanto, Siemens Healthcare), using individual circulation time determined by a test bolus, was performed. Steady state imaging was performed using an isometric spatial resolution of 1.0 mm. Image quality was rated. Each vascular segment in MR angiography was evaluated by 2 independent and blinded reviewers and the stenosis degree was compared with the preferred standard-of-reference, using a 5-point scale. Differences between first pass and combined MR angiography were assessed with a 95% confidence interval (CI) by applying the adjusted modified chi(2) test. Changes in therapy based on the whole-body examination strategy were evaluated. RESULTS: The number of nondiagnostic territories was 24 of 197 (12.2%) for first pass MR angiography and decreased to 3 of 197 (1.5%) after addition of steady state MR angiography. The diagnostic accuracy for quantification of arterial stenosis in combined MR angiography (94.7%; 95% CI: 92.4-97.1) was superior to first pass MR angiography (81.7%; 95% CI: 73.7-89.8; statistically significant). Patient management was changed in 12 of 49 patients, in 7 of 12 patients the change was applied to an additional lesion detected by the whole-body examination strategy. CONCLUSION: The quantification and detection of arterial stenosis is improved by the steady state high-resolution gadofosveset trisodium-enhanced MR angiography. Additional lesions detected by whole-body examination strategy or differences in stenosis quantification may lead to changes in therapy.

The C-terminal tail of CRTH2 is a key molecular determinant that constrains Galphai and downstream signaling cascade activation.

Prostaglandin D(2) activation of the seven-transmembrane receptor CRTH2 regulates numerous cell functions that are important in inflammatory diseases, such as asthma. Despite its disease implication, no studies to date aimed at identifying receptor domains governing signaling and surface expression of human CRTH2. We tested the hypothesis that CRTH2 may take advantage of its C-tail to silence its own signaling and that this mechanism may explain the poor functional responses observed with CRTH2 in heterologous expression systems. Although the C terminus is a critical determinant for retention of CRTH2 at the plasma membrane, the presence of this domain confers a signaling-compromised conformation onto the receptor. Indeed, a mutant receptor lacking the major portion of its C-terminal tail displays paradoxically enhanced Galpha(i) and ERK1/2 activation despite enhanced constitutive and agonist-mediated internalization. Enhanced activation of Galpha(i) proteins and downstream signaling cascades is probably due to the inability of the tail-truncated receptor to recruit beta-arrestin2 and undergo homologous desensitization. Unexpectedly, CRTH2 is not phosphorylated upon agonist-stimulation, a primary mechanism by which GPCR activity is regulated. Dynamic mass redistribution assays, which allow label-free monitoring of all major G protein pathways in real time, confirm that the C terminus inhibits Galpha(i) signaling of CRTH2 but does not encode G protein specificity determinants. We propose that intrinsic CRTH2 inhibition by its C terminus may represent a rather unappreciated strategy employed by a GPCR to specify the extent of G protein activation and that this mechanism may compensate for the absence of the classical phosphorylation-dependent signal attenuation.

CT-based patient-specific modeling of glenoid rim defects: a feasibility study.

OBJECTIVE: Reconstruction of glenoid bone defects requires accurate preoperative planning. The purpose of this study is to present a method for quantifying the defect size and generating a 3D model of the bone graft for augmentation by matching the fractured glenoid with the contralateral side. MATERIALS AND METHODS: Ten paired shoulders from five cadavers (subjects: three women and two men; mean age, 85 years) and 60 paired shoulders in 30 patients (controls: nine women and 21 men; mean age, 21 years) were examined using CT to determine bilateral comparability by assessment of the maximum glenoid diameters, surface area, and volume. After creation of a glenoid rim defect in the study group, repeated CT scans were superimposed with the data from the contralateral side. The defect size was quantified and the missing fragment virtually reconstructed. Accuracy was evaluated by comparing the virtually repaired glenoid with the predefect CT scan. RESULTS: There were no significant side-to-side differences in intact shoulders (p < 0.05). After creation of the glenoid defects, there was a mean decrease of 31% in the anteroposterior diameter, 34% in surface area, and 19% in volume. The virtually reconstructed glenoids did not differ significantly from the predefect CT scans. The averaged predefect-to-postdefect difference was 3% for the anteroposterior diameter (R(2) = 0.71), 6% for the surface area (R(2) = 0.82), and 4% for the volume (R(2) = 0.98). CONCLUSION: A precise 3D model of the glenoid bony defect can be generated. The computer simulation provides a virtual model of the bone graft, which may potentially improve arthroscopic bone augmentation.