bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Evaluation of Extension Capacity of the Occipitoatlantoaxial Complex in Patients with Rheumatoid Arthritis
Authors: Takenaka Ichiro , Iwagaki Tamao , Aoyama Kazuyoshi , Ishimura Hiroshi , Kadoya Tatsuo
Published: March 2006

Background

The authors devised a new method, the hyomental distance ratio (HMDR), for preoperatively identifying patients with a reduced occipitoatlantoaxial extension capacity, which was defined as the ratio of the hyomental distance in head extension position to that in the neutral position. They compared the accuracy of the HMDR with that of the Bellhouse test in 40 patients with rheumatoid arthritis.

Methods

Each patient wearing goggles on which a goniometer was mounted sat upright with the head in the neutral position and then extended the head maximally. The angle of the goggles and the hyomental distance were measured in the two head positions, and a lateral cervical radiograph was taken simultaneously. The Bellhouse angle was defined as a difference in the angles of the goggles between these positions.

Results

Median values of the radiologic occipitoatlantoaxial extension angle and the Bellhouse angle were 11.2 degrees and 24.9 degrees , respectively. In 21 of 40 patients, the radiologic occipitoatlantoaxial extension angle was less than 12 degrees (reduced occipitoatlantoaxial extension capacity). In these patients, extension of the median angle of 16.4 degrees occurred at the subaxial regions and was greater than that of 8.5 degrees in patients with a radiologic occipitoatlantoaxial extension angle of 12 degrees or more (P < 0.01). As a result, a strong relation between the Bellhouse angle and radiologic occipitoatlantoaxial extension angle was not established (P < 0.01, r = 0.48). In contrast, the HMDR correlated well with the radiologic occipitoatlantoaxial extension angle (P < 0.0001, r = 0.88). The areas under the receiver operating characteristic curve of the Bellhouse test and the HMDR were 0.72 and 0.95, respectively.

Conclusions

The HMDR was a good predictor of a reduced occipitoatlantoaxial extension capacity in patients with rheumatoid arthritis, but the Bellhouse test was not a clinically reliable method.
An Evaluation of Transcutaneous Carbon Dioxide Partial Pressure Monitoring during Apnea Testing in Brain-dead Patients
Authors: Vivien Benoîit , Marmion Frédéric , Roche Sabine , Devilliers Catherine , Langeron Olivier , Coriat Pierre , Riou Bruno
Published: March 2006

Background

Diagnosis of brain death usually requires an arterial carbon dioxide partial pressure (Paco2) of 60 mmHg during the apnea test, but the increase in Paco2 is unpredictable. The authors evaluated whether transcutaneous carbon dioxide partial pressure (Ptcco2) monitoring during apnea test can predict that a Paco2 of 60 mmHg has been reached.

Methods

The authors compared Ptcco2 measured with a transcutaneous ear sensor (V-Sign Sensor, Sentec Digital Monitoring System; SENTEC-AG, Therwil, Switzerland) and Paco2 obtained from arterial blood gas measurements in 32 clinically brain-dead patients.

Results

In the first 20 patients, the mean Paco2-Ptcco2 gradient was 0.7 +/- 3.6 mmHg at baseline and 8.7 +/- 7.1 mmHg after 20 min of apnea. Using receiver operating characteristic curve analysis (area under the curve: 0.983 +/- 0.013), the best threshold value of Ptcco2 to predict that a Paco2 of 60 mmHg had been reached was 60 mmHg (positive predictive value: 1.00 [0.93-1.00]). In the following 12 patients investigated with use of this Ptcco2 target value of 60 mmHg, the mean duration of the apnea test (11 +/- 4 vs. 20 +/- 0 min; P < 0.001), hypercapnia (74.0 +/- 4.9 vs. 98.3 +/- 20.0 mmHg; P < 0.001), acidosis (pH: 7.18 +/- 0.06 vs. 7.11 +/- 0.08; P < 0.001), and decrease in arterial oxygen partial pressure (-47 +/- 44 vs. -95 +/- 89; P < 0.05) at the end of the test were reduced as compared with the 20-min apnea test group.

Conclusion

During the apnea test in brain-dead patients, a Ptcco2 of 60 mmHg accurately predicts that a Paco2 of 60 mmHg has been reached. This may allow a reduction in the duration of the apnea test and consecutively limit occurrence of complications.
Reversal of Profound Rocuronium Neuromuscular Blockade by Sugammadex in Anesthetized Rhesus Monkeys
Authors: de Boer Hans D. , van Egmond Jan , van de Pol Francien , Bom Anton , Booij Leo H. D. J.
Published: March 2006

Background

Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic gamma-cyclodextrin derivative. The current study determined the feasibility of reversal of rocuronium-induced profound neuromuscular blockade with sugammadex in the anesthetized rhesus monkey using train-of-four stimulation.

Methods

Four female rhesus monkeys each underwent three experiments. In each experiment, first, a 100-microg/kg dose of rocuronium was injected and spontaneous recovery was monitored. After full recovery, a 500-microg/kg dose of rocuronium was injected. Up to this point, all three experiments in a single monkey were identical. One minute after this rocuronium injection, either one of the two tested dosages of sugammadex (1.0 or 2.5 mg/kg) was injected or saline was injected.

Results

Injection of 100 microg/kg rocuronium resulted in a mean neuromuscular blockade of 93.0% (SD = 4%), and profound blockade was achieved by injection of 500 microg/kg. In all experiments, a 100% neuromuscular blockade was achieved at this dose. After injection of the high rocuronium dose, the 90% recovery of the train-of-four ratio took 28 min (SD = 7 min) after saline, 26 min (SD = 9.5 min) after 1 mg/kg sugammadex, and 8 min (SD = 3.6 min) after 2.5 mg/kg sugammadex. Signs of residual blockade or recurarization were not observed. Injection of sugammadex had no significant effects on blood pressure or heart rate.

Conclusions

Chemical encapsulation of rocuronium by sugammadex is a new therapeutic mechanism allowing effective and rapid reversal of profound neuromuscular blockade induced by rocuronium in anesthetized rhesus monkeys.
Activation and Inhibition of Human Muscular and Neuronal Nicotinic Acetylcholine Receptors by Succinylcholine
Authors: Jonsson Malin , Dabrowski Michael , Gurley David A. , Larsson Olof , Johnson Edwin C. , Fredholm Bertil B. , Eriksson Lars I.
Published: March 2006

Background

Succinylcholine is one of the most widely used muscle relaxants in clinical anesthesia and emergency medicine. Although the clinical advantages and cardiovascular side effects are well known, its mechanism of action within the human nicotinic cholinergic receptor system remains to be understood. The aim of this study was to investigate the effect of succinylcholine on human muscle and neuronal nicotinic acetylcholine receptor (nAChR) subtypes.

Methods

Xenopus laevis oocytes were injected with human messenger RNA for muscle and neuronal nAChR subunits. Receptor activation, desensitization, and inhibition induced by the natural ligand acetylcholine or by succinylcholine was studied using a multichannel two-electrode voltage clamp setup. Responses were measured as peak current and net charge.

Results

Succinylcholine concentration-dependently activated the muscle-type nAChR with an EC50 value of 10.8 microm (95% confidence interval, 9.8-11.9 microm), and after the initial activation, succinylcholine desensitized the muscle-type nAChR. Succinylcholine did not activate the neuronal nAChR subtypes alpha3beta2, alpha3beta4, alpha4beta2, or alpha7 at concentrations up to 1 mm and was a poor inhibitor at these receptor subtypes, with IC50 values above 100 microm.

Conclusion

Succinylcholine activates the muscle-type nAChR followed by desensitization. The observation that succinylcholine does not inhibit the presynaptic alpha3beta2 autoreceptor at clinically relevant concentrations provides a possible mechanistic explanation for the typical lack of tetanic fade in succinylcholine-induced neuromuscular blockade. Finally, cardiovascular side effects (e.g., tachyarrhythmias) of succinylcholine are not mediated via direct activation of the autonomic ganglionic alpha3beta4 subtype because succinylcholine does not activate the neuronal nAChRs.
Comparison of Arginine Vasopressin, Terlipressin, or Epinephrine to Correct Hypotension in a Model of Anaphylactic Shock in Anesthetized Brown Norway Rats
Authors: Dewachter Pascale , Jouan-Hureaux Valérie , Lartaud Isabelle , Bello Gaëlle , de Talancé Nicole , Longrois Dan , Mertes Paul Michel
Published: March 2006

Background

Arginine vasopressin (AVP) and terlipressin were proposed as alternatives to catecholamines in shock states characterized by decreased plasma AVP concentrations. The endogenous plasma AVP profile in anaphylactic shock is unknown. In an ovalbumin-sensitized anesthetized anaphylactic shock rat model, the authors investigated (1) plasma AVP concentrations and (2) the dose versus mean arterial pressure response for exogenous AVP and terlipressin and compared them with those of epinephrine.

Methods

In a first series of rats (n = 12), endogenous plasma AVP concentrations were compared with a model of pharmacologically induced hypotension (nicardipine, n = 12). A second series was randomly assigned to three groups (AVP, n = 7; terlipressin, n = 7; epinephrine, n = 7) and dose (AVP: 8 doses, 0.03-100 U/kg; terlipressin: 7 doses, 0.03-30 microg/kg; epinephrine: 7 doses, 0.3-300 microg/kg)-response mean arterial pressure curves were plotted. Data are expressed as mean +/- SD.

Results

Endogenous plasma AVP concentrations were significantly lower in anaphylactic shock (57 +/- 26 pg/ml) than in the nicardipine group (91 +/- 43 pg/ml; P < 0.05). The ED50 was 10.6 microg/kg (95% confidence interval, 7.1-15.9) for epinephrine and 4.1 U/kg (95% confidence interval, 3.0-5.6) for AVP. Terlipressin did not change mean arterial pressure, regardless of the dose used.

Conclusions

In a rat model, anaphylactic shock is associated with inadequately low plasma AVP concentrations. For clinically relevant doses, AVP and epinephrine had comparable effects on mean arterial pressure and heart rate values, whereas, unexpectedly, terlipressin was ineffective. These results are consistent with reports in humans experiencing anaphylaxis where AVP injection restored arterial pressure.
The Well-being Model
Authors: Zanderigo Eleonora , Sartori Valentina , Sveticic Gorazd , Bouillon Thomas , Schumacher Peter , Morari Manfred , Curatolo Michele
Published: March 2006

Background

Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods

By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results

Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.

Conclusions

The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.
Propofol Inhibits Phosphorylation of N -methyl-d-aspartate Receptor NR1 Subunits in Neurons
Authors: Kingston Seth , Mao Limin , Yang Lu , Arora Anish , Fibuch Eugene E. , Wang John Q.
Published: March 2006

Background

Anesthetics may interact with ionotropic glutamate receptors to produce some of their biologic actions. Cellular studies reveal that the ionotropic glutamate receptors, N-methyl-D-aspartate receptors (NMDARs), can be phosphorylated on their NR1 subunits at the C-terminal serine residues, which is a major mechanism for the regulation of NMDAR functions. It is currently unknown whether anesthetics have any modulatory effects on NMDAR NR1 subunit phosphorylation.

Methods

The possible effect of a general anesthetic propofol on phosphorylation of NR1 subunits at serine 897 (pNR1S897) and 896 (pNR1S896) was detected in cultured rat cortical neurons.

Results

Propofol consistently reduced basal levels of pNR1S897 and pNR1S896 in a concentration-dependent manner. This reduction was rapid as the reliable reduction of pNR1S896 developed 1 min after propofol administration. Pretreatment of cultures with the protein phosphatase 2A inhibitors okadaic acid or calyculin A blocked the effect of propofol on the NR1 phosphorylation, whereas okadaic acid or calyculin A alone did not alter basal pNR1S897 and pNR1S896 levels. In addition, propofol decreased tyrosine phosphorylation of protein phosphatase 2A at tyrosine 307, resulting in an increase in protein phosphatase 2A activity. In the presence of propofol, the NMDAR agonist-induced intracellular Ca2+ increase was impaired in neurons with dephosphorylated NR1 subunits.

Conclusions

Together, these data indicate an inhibitory effect of a general anesthetic propofol on NMDAR NR1 subunit phosphorylation in neurons. This inhibition was mediated through a signaling mechanism involving activation of protein phosphatase 2A.
Xenon Impairs Neurocognitive and Histologic Outcome after Cardiopulmonary Bypass Combined with Cerebral Air Embolism in Rats
Authors: Jungwirth Bettina , Gordan M Lucia , Blobner Manfred , Schmehl Wolfgang , Kochs Eberhard F. , Mackensen G Burkhard
Published: March 2006

Background

The neuroprotective properties of xenon may improve cerebral outcome after cardiac surgery using cardiopulmonary bypass (CPB). However, its disposition to expand gaseous bubbles that during CPB present as cerebral air emboli (CAE) could abolish any beneficial effect or even worsen cerebral outcome. Therefore, the authors studied the impact of xenon on neurologic, cognitive, and histologic outcome after CPB combined with CAE in rats.

Methods

With institutional review board approval, 40 rats were assigned to four groups (n = 10). In two CPB-CAE groups, rats were subjected to 90 min of normothermic CPB with 10 repetitively administered CAEs (0.3 microl/bolus). Rats in two sham groups were not exposed to CPB and CAE. Groups were further subdivided into xenon (56%; 20 min before, during, and 30 min after CPB) and nitrogen groups. Neurologic and cognitive function was tested until postoperative day 14, when cerebral infarct volumes were determined.

Results

Animals of the CPB-CAE groups showed transient deficits in gross neurologic function. Further, rats of the CPB-CAE-xenon group demonstrated impaired fine motor and cognitive performance persisting until postoperative day 14. Consistently, infarct volumes were larger in the CPB-CAE-xenon group compared with the CPB-CAE-nitrogen group (P = 0.03).

Conclusions

This is the first demonstration in which the neurologic effects of CAE have been examined in a rat model of CPB. Xenon exposure aggravated the neurologic dysfunction that is produced by CAE during CPB; potential neuroprotective effects of xenon may have been masked by the effects of xenon on CAE.
Isoflurane, but Not Sevoflurane, Increases Transendothelial Albumin Permeability in the Isolated Rat Lung
Authors: Hu Guochang , Schwartz David E. , Shajahan Ayesha N. , Visintine David J. , Salem M Ramez , Crystal George J. , Albrecht Ronald F. , Vogel Stephen M. , Minshall Richard D.
Published: March 2006

Background

Caveolae mediated transendothelial transport of albumin has recently been shown to be the primary mechanism regulating microvascular endothelial albumin permeability. The authors investigated the effects of isoflurane and sevoflurane on pulmonary endothelial albumin permeability and assessed the potential role of the caveolae scaffold protein, caveolin-1, in these effects.

Methods

Isolated rat lungs and cultured rat lung microvessel endothelial cells (RLMVECs) were exposed to 1.0 or 2.0 minimum alveolar concentration (MAC) isoflurane or sevoflurane for 30 min. I-albumin permeability-surface area product and capillary filtration coefficient were determined in the isolated lungs. In RLMVECs, uptake and transendothelial transport of I-albumin were measured in the absence and presence of pretreatment with 2 mm methyl-beta-cyclodextrin, a caveolae-disrupting agent. Uptake of fluorescent-labeled albumin, as well as phosphorylation of Src kinase and caveolin-1, was also determined. In Y14F-caveolin-1 mutant (nonphosphorylatable) expressing RLMVECs, uptake of I-albumin and phosphorylation of caveolin-1 were evaluated.

Results

In the isolated lungs, 2.0 MAC isoflurane increased I-albumin permeability-surface area product by 48% without affecting capillary filtration coefficient. In RLMVECs, isoflurane more than doubled the uptake of I-albumin and caused a 54% increase in the transendothelial transport of I-albumin. These effects were blocked by pretreatment with methyl-beta-cyclodextrin. The isoflurane-induced increase in uptake of I-albumin in wild-type RLMVECs was abolished in the Y14F-caveolin-1 mutant expressing cells. Isoflurane also caused a twofold increase in Src and caveolin-1 phosphorylation. Neither 1.0 MAC isoflurane nor 1.0 or 2.0 MAC sevoflurane affected any index of albumin transport or phosphorylation of caveolin-1.

Conclusion

Isoflurane, but not sevoflurane, increased lung transendothelial albumin permeability through enhancement of caveolae-mediated albumin uptake and transport in the isolated lung. This effect may involve an enhanced phosphorylation of caveolin-1.
Intravenous Anesthetics Inhibit Capacitative Calcium Entry in Pulmonary Venous Smooth Muscle Cells
Authors: Shimizu Sachiko , Ding Xueqin , Murray Paul A.
Published: March 2006

Background

The authors have previously demonstrated that propofol attenuates capacitative calcium entry (CCE) via the protein kinase C signaling pathway in pulmonary artery smooth muscle cells (PVSMCs). The current goals were to determine whether CCE exists in PVSMCs; to assess the roles of the protein kinase C, tyrosine kinase (TK), and rho-kinase signaling pathways in regulating CCE; and to investigate the extent and cellular mechanisms by which intravenous anesthetics (thiopental, midazolam, ketamine, and propofol) alter CCE.

Methods

Primary cultures of fura-2-loaded canine PVSMCs were placed in a dish (37 degrees C) on an inverted fluorescence microscope. Intracellular Ca2+ concentration ([Ca2+]i) was measured as the 340/380 fluorescence ratio in individual PVSMCs. Thapsigargin, a sarcoplasmic reticulum Ca2+-adenosine triphosphatase inhibitor, was used to deplete intracellular Ca2+ stores after removing extracellular Ca2+. CCE was then activated by restoring extracellular Ca2+ (2.2 mm).

Results

Thapsigargin caused a transient increase in [Ca2+]i (160 +/- 6%). Restoring extracellular Ca2+ caused a rapid peak increase in [Ca2+]i (155 +/- 7% of baseline), followed by a sustained increase in [Ca2+]i (129 +/- 5% of baseline), i.e., CCE was stimulated in PVSMCs. Neither protein kinase C activation nor inhibition had an effect on CCE. rho-Kinase inhibition also had no effect on CCE, whereas TK inhibition attenuated both peak and sustained CCE. Thiopental, midazolam, ketamine, and propofol each attenuated both peak and sustained CCE. TK inhibition abolished the thiopental-, midazolam-, and ketamine-induced, but not the propofol-induced, decreases in CCE.

Conclusion

Capacitative calcium entry is present in canine PVSMCs. Thiopental, midazolam, and ketamine attenuate CCE primarily via the TK signaling pathway. Propofol attenuates CCE via a TK-independent mechanism.
Bupivacaine Inhibits Activation of Neuronal Spinal Extracellular Receptor–activated Kinase through Selective Effects on Ionotropic Receptors
Authors: Yanagidate Fumi , Strichartz Gary R.
Published: March 2006

Background

Central terminals of primary nociceptors release neurotransmitters glutamate and substance P, which bind to ionotropic or metabotropic receptors on spinal neurons to induce cellular responses. Extracellular signal-regulated kinases are activated by these receptors and are important modulators of pain at the dorsal horn. The authors investigated these pathways as potential targets for antinociceptive actions of local anesthetics.

Methods

The effects of bupivacaine on the activation of extracellular receptor-activated kinase (phosphorylation to pERK) in rat spinal cord slices, induced by presynaptic release (capsaicin), by presynaptic or postsynaptic ionotropic or metabotropic receptor activation, or by activation of intracellular protein kinase C or protein kinase A and also by a receptor-independent Ca2+ ionophore, were quantitated by immunohistochemistry, counting pERK-positive neurons in the superficial dorsal horn.

Results

Capsaicin (3 microm, 10 min)-stimulated pERK was reduced by bupivacaine (IC50 approximately 2 mm, approximately 0.05%), which similarly suppressed pERK induced by the ionotropic glutamate receptors for N-methyl-D-aspartate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid but not that induced by the metabotropic receptors for glutamate, bradykinin, or substance P. Extracellular receptor-activated kinase activation by the Ca2+ ionophore ionomycin was also sensitive to bupivacaine, but direct activation by protein kinase A or protein kinase C was not.

Conclusions

Bupivacaine inhibits pERK activation resulting from different modes of Ca2+ influx through the plasma membrane. This represents a postsynaptic mechanism of analgesia that occurs in parallel with impulse inhibition during neuraxial blockade.
Subpopulation of Dorsal Horn Neurons Displays Enhanced N -methyl-d-aspartate Receptor Function after Chronic Morphine Exposure
Authors: Zhao Min , Joo Daisy Therese
Published: March 2006

Background

Morphine tolerance may be attributed to enhancement of glutamatergic neurotransmission, in particular to increased function of the N-methyl-D-aspartate (NMDA) receptor. The cellular mechanisms responsible for these changes remain poorly defined. The authors identified and characterized a specific subpopulation of dorsal horn neurons, displaying NMDA receptor plasticity in response to chronic morphine administration.

Methods

The authors undertook current clamped and voltage clamped recordings of NMDA receptor-mediated responses from cultured rat dorsal horn neurons that were untreated or treated for 7 days with 1 or 100 microm morphine.

Results

Smaller (capacitance < or = 22 pF), tonic firing neurons showed a significantly enhanced NMDA receptor-mediated peak current after prolonged morphine treatment, whereas larger and phasic firing neurons showed no enhancement. With high-concentration but not low-concentration morphine treatment, Mg2+ blockade of NMDA receptors at resting membrane potentials was reduced. Furthermore, the chronic opioid-induced increase in NMDA current was attenuated by pretreatment with either a mu-opioid receptor inhibitor (naloxone) or an NMDA receptor inhibitor (2-amino-5-phosphonovalerate) (low-concentration > high-concentration morphine).

Conclusions

In an electrophysiologically defined subpopulation of dorsal horn neurons, enhanced NMDA receptor function after chronic morphine exposure was shown to be mechanistically dependent on morphine concentration and sensitive to both NMDA and mu-opioid receptor antagonism. Therefore, these changes observed in this population of sensory spinal neurons can be used to study the development and prevention of opioid tolerance described in multiple laboratory and clinical reports.
Predicting Patient Nonappearance for Surgery as a Scheduling Strategy to Optimize Operating Room Utilization in a Veterans' Administration Hospital
Authors: Basson Marc D. , Butler Timothy W. , Verma Harish
Published: March 2006

Background

Previous attempts at improving operating room utilization have generally emphasized more accurate scheduling, starting the first case on time, and reducing turnover time. Surgical case cancellations have largely been ignored except for recommendations for preoperative screening and good physician-patient communication to improve patient compliance.

Methods

A retrospective review of operating room records was initially used to identify reasons for surgical cancellations. This was followed by a retrospective stratified case-control study of patient records to identify preexisting factors that predict the failure of patients to appear for surgical procedures as scheduled. Factors assessed included demographics, type of surgical procedure, compliance with previous healthcare visits, substance abuse, mental illness, travel distance, and neurologic problems.

Results

The authors reviewed their operating room utilization and found patient nonappearance rates to be a substantial source of surgical cancellations. Furthermore, multivariate analysis demonstrated that patient nonappearance could be strongly predicted from patient noncompliance with clinic visits and other clinical procedures without reference to the other variables assessed. Further analysis of data from an independent sample of patients confirmed this observation.

Conclusions

Noncompliance with hospital visits for surgical procedures can be predicted from noncompliance with other healthcare encounters. Surgical procedures for previously noncompliant patients should be booked at the end of the operating room day, when the cancellation is least likely to interfere with operating room flow.
Chipping into the human genome: novel insights for transplantation
Authors: Sarwal Minnie M.
Published: March 2006

Summary: High throughput, high density platforms for transcriptional, proteomic, and metabonomic analyses are opening new doors for improving our understanding of the complexity and redundancy of the immune system in the interplay of the innate and allo‐immune responses in organ transplantation. New insights are being obtained into the possible discrepancies between the gold standard of tissue pathological diagnosis and clinical graft outcomes, as new transcriptional categories of transplant rejection evolve. The bystander effects of chronic immunosuppression underlying the complexities of graft dysfunction are beginning to be understood. Non‐invasive mechanisms to monitor transplants, by following ‘footprints’ of biomarker sets that reflect the disease phenotype, are being pursued for their clinical application for direct patient care. Utilization of these same biomarker sets may also offer a unique means to titrate immunosuppression and predict specific graft dysfunction events prior to clinical decline, thus bringing in the potential to reduce patient morbidity from infection and malignancy, preserve graft integrity, and limit the progression of chronic graft injury. Bioinformatics support is integral to the unraveling of the mysteries of the human genome, proteome, and metabolome in disease and in health.
Microarray‐based understanding of normal and malignant plasma cells
Authors: De Vos John , Hose Dirk , Rème Thierry , Tarte Karin , Moreaux Jérôme , Mahtouk Karéne , Jourdan Michel , Goldschmidt Hartmut , Rossi Jean‐François , Cremer Friedrich W. , Klein Bernard
Published: March 2006

Summary:  Plasma cells (PCs) develop from B lymphocytes following stimulation by antigen and express a genetic program aimed at the synthesis of immunoglobulins. This program includes the induction of genes coding for transcription factors such as PRDM1, X‐box‐binding protein 1 and BHLHB3, cell‐surface molecules such as CD138/syndecan‐1, and for the unfolded protein response. We review how the microarray technology has recently contributed to the understanding of the biology of this rare but essential cell population and its transformation into premalignant and malignant PCs.
The use of genomewide ENU mutagenesis screens to unravel complex mammalian traits: identifying genes that regulate organ‐specific and systemic autoimmunity
Authors: Hoyne Gerard F. , Goodnow Christopher C.
Published: March 2006

Summary:  T‐cell development is perhaps one of the best understood processes of mammalian cell differentiation, as many of the genes and pathways have been identified. By contrast, relatively little is known about the genes and pathways involved in immunological tolerance to self‐antigens. Here, we describe the challenges associated with a genomewide screen designed at identifying new immune regulatory genes that uses a model of organ‐specific autoimmunity leading to type 1 diabetes. The successful propagation and identification of the new gene variants will shed light on the various developmental checkpoints in lymphocyte development that are crucial for establishing tolerance to self‐antigens.
Use of baculovirus MHC/peptide display libraries to characterize T‐cell receptor ligands
Authors: Crawford Frances , Jordan Kimberly R. , Stadinski Brian , Wang Yibing , Huseby Eric , Marrack Philippa , Slansky Jill E. , Kappler John W.
Published: March 2006

Summary:  Peptide/protein display libraries are powerful tools for identifying and manipulating receptor/ligand pairs. While the large size of bacterial phage display libraries has made them the platform of choice in many applications, often considerable engineering has been required to achieve display of properly folded and active eukaryotic proteins, such as antibodies. This problem has been partially solved in several eukaryotic display systems, e.g. using yeast or retroviruses, but these systems have their own limitations. Recently, baculovirus has been developed as a display system using the virus itself or infected insect cells as the display platform. Here, we review the development and use of baculovirus‐infected cells as a platform for display libraries of peptides bound to major histocompatibility complex (MHC) class I (MHCI) or class II (MHCII). We have used fluorescent multimeric soluble T‐cell receptors (TCRs) to screen these libraries and to identify peptide antigen mimotopes. We also present some improvements to this system that allow very large libraries to be constructed and screened. We have used these libraries to examine the role of MHCII‐bound peptides in the presentation of the staphylococcal enterotoxin A (SEA) and to manipulate an MHCI tumor‐associated antigen.
The plasticity of immunoglobulin gene systems in evolution
Authors: Hsu Ellen , Pulham Nicolas , Rumfelt Lynn L. , Flajnik Martin F.
Published: March 2006

Summary:  The mechanism of recombination‐activating gene (RAG)‐mediated rearrangement exists in all jawed vertebrates, but the organization and structure of immunoglobulin (Ig) genes, as they differ in fish and among fish species, reveal their capability for rapid evolution. In systems where there can exist 100 Ig loci, exon restructuring and sequence changes of the constant regions led to divergence of effector functions. Recombination among these loci created hybrid genes, the strangest of which encode variable (V) regions that function as part of secreted molecules and, as the result of an ancient translocation, are also grafted onto the T‐cell receptor. Genomic changes in V‐gene structure, created by RAG recombinase acting on germline recombination signal sequences, led variously to the generation of fixed receptor specificities, pseudogene templates for gene conversion, and ultimately to Ig sequences that evolved away from Ig function. The presence of so many Ig loci in fishes raises interesting questions not only as to how their regulation is achieved but also how successive whole‐locus duplications are accommodated by a system whose function in other vertebrates is based on clonal antigen receptor expression.
Gene expression profiling in human autoimmunity
Authors: Baechler Emily C. , Batliwalla Franak M. , Reed Ann M. , Peterson Erik J. , Gaffney Patrick M. , Moser Kathy L. , Gregersen Peter K. , Behrens Timothy W.
Published: March 2006

Summary:  Human autoimmune diseases are well suited for the application of gene expression profiling. Sampling of blood cells and target tissues has already revealed many important pathways contributing to this spectrum of disorders, and many commonalities are emerging. For instance, clinically distinct diseases such as systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, and psoriasis all show evidence for dysregulation of the type I interferon pathway. These data suggest that autoimmune diseases will eventually be categorized at the level of gene expression. This work has led to advances in our understanding of disease pathogenesis and in the future promises to facilitate assessments of disease activity and improve targeting of therapies. Here, we review the literature on gene profiling in human autoimmune diseases and provide perspective on the current state of the art.
Charting protein complexes, signaling pathways, and networks in the immune system
Authors: Bauch Angela , Superti‐Furga Giulio
Published: March 2006

Summary:  Systematic deciphering of protein–protein interactions has the potential to generate comprehensive and instructive signaling networks and to fuel new therapeutic and diagnostic strategies. Here, we describe how recent advances in high‐throughput proteomic technologies, involving biochemical purification methods and mass spectrometry analysis, can be applied systematically to the characterization of protein complexes and the computation of molecular networks. The networks obtained form the basis for further functional analyses, such as knockdown by RNA interference, ultimately leading to the identification of nodes that represent candidate targets for pharmacological exploitation. No individual experimental approach can accurately elucidate all critical modulatory components and biological aspects of a signaling network. Such functionally annotated protein–protein interaction networks, however, represent an ideal platform for the integration of additional datasets. By providing links between molecules, they also provide links to all previous observations associated with these molecules, be they of genetic, pharmacological, or other origin. As exemplified here by the analysis of the tumor necrosis factor (TNF)‐α/nuclear factor‐κB (NF‐κB) signaling pathway, the approach is applicable to any mammalian cellular signaling pathway in the immune system.
Transcriptional basis of lymphocyte tolerance
Authors: Borde Madhuri , Barrington Robert A. , Heissmeyer Vigo , Carroll Michael C. , Rao Anjana
Published: March 2006

Summary:  Signaling through lymphocyte antigen receptors has the potential to initiate several distinct outcomes: proliferation, differentiation, apoptosis, or functional unresponsiveness. Expansion and differentiation of effector T cells is required for defense against foreign antigens, whereas functional unresponsiveness, termed anergy, is a cell‐intrinsic mechanism that contributes to peripheral self‐tolerance. Other mechanisms of peripheral tolerance include the ‘dominant’ tolerance imposed by regulatory T cells and immunosuppression mediated by interleukin‐10 and transforming growth factor‐β. T‐ and B‐cell antigen receptor ligation induces an increase in intracellular calcium levels as well as activating additional signaling pathways that are further potentiated by costimulatory receptors. In this review, we argue that cell‐intrinsic programs of peripheral anergy and tolerance are imposed by sustained calcium signaling in lymphocytes. We address in particular the role of the calcium‐dependent transcription factor nuclear factor for activation of T cells, which is activated by antigen receptor stimulation and, depending on the presence or absence of input from its transcriptional partner, activator protein‐1, dictates two distinct transcriptional programs: activation or tolerance.
Identifying susceptibility genes for immunological disorders: patterns, power, and proof
Authors: Plenge Robert , Rioux John D.
Published: March 2006

Summary:  There is a genetic basis to the most common immune‐mediated diseases. Identifying disease susceptibility genes, however, has been a challenge. Only a few genes have been consistently replicated across multiple studies. These convincing examples provide insight into a genetic approach to common immune diseases as well as insight into disease pathogenesis. Here, we discuss several important concepts of a genetic study – patterns, power, and proof – and why these are germane in testing inherited variation for influence on disease. Recent developments in the fields of human genetics and genomics are overcoming limitations within the field, and we anticipate many exciting discoveries in the near future.
A Plaidoyer for ‘Systems Immunology’
Authors: Benoist Christophe , Germain Ronald N. , Mathis Diane
Published: March 2006

Summary:  A complete understanding of the immune system will ultimately require an integrated perspective on how genetic and epigenetic entities work together to produce the range of physiologic and pathologic behaviors characteristic of immune function. The immune network encompasses all of the connections and regulatory associations between individual cells and the sum of interactions between gene products within a cell. With 30 000+ protein‐coding genes in a mammalian genome, further compounded by microRNAs and yet unrecognized layers of genetic controls, connecting the dots of this network is a monumental task. Over the past few years, high‐throughput techniques have allowed a genome‐scale view on cell states and cell‐ or system‐level responses to perturbations. Here, we observe that after an early burst of enthusiasm, there has developed a distinct resistance to placing a high value on global genomic or proteomic analyses. Such reluctance has affected both the practice and the publication of immunological science, resulting in a substantial impediment to the advances in our understanding that such large‐scale studies could potentially provide. We propose that distinct standards are needed for validation, evaluation, and visualization of global analyses, such that in‐depth descriptions of cellular responses may complement the gene/factor‐centric approaches currently in favor.
Circuitry of nuclear factor κB signaling
Authors: Hoffmann Alexander , Baltimore David
Published: March 2006

Summary:  Over the past few years, the transcription factor nuclear factor (NF)‐κB and the proteins that regulate it have emerged as a signaling system of pre‐eminent importance in human physiology and in an increasing number of pathologies. While NF‐κB is present in all differentiated cell types, its discovery and early characterization were rooted in understanding B‐cell biology. Significant research efforts over two decades have yielded a large body of literature devoted to understanding NF‐κB's functioning in the immune system. NF‐κB has been found to play roles in many different compartments of the immune system during differentiation of immune cells and development of lymphoid organs and during immune activation. NF‐κB is the nuclear effector of signaling pathways emanating from many receptors, including those of the inflammatory tumor necrosis factor and Toll‐like receptor superfamilies. With this review, we hope to provide historical context and summarize the diverse physiological functions of NF‐κB in the immune system before focusing on recent advances in elucidating the molecular mechanisms that mediate cell type‐specific and stimulus‐specific functions of this pleiotropic signaling system. Understanding the genetic regulatory circuitry of NF‐κB functionalities involves system‐wide measurements, biophysical studies, and computational modeling.
The Evolution and Evolvability of Culture
Authors: Sterelny Kim
Published: March 2006

Abstract: In this paper I argue, first, that human lifeways depend on cognitive capital that has typically been built over many generations. This process of gradual accumulation produces an adaptive fit between human agents and their environments; an adaptive fit that is the result of hidden‐hand, evolutionary mechanisms. To explain distinctive features of human life, we need to understand how cultures evolve. Second, I distinguish a range of different evolutionary models of culture. Third, I argue that none of meme‐based models, dual inheritance models, nor Boyd and Richerson's models fully succeed in explaining this adaptive fit between agent and the world. I then briefly develop an alternative. Finally, I explore (in a preliminary way) constraints on cultural adaptation. The processes of cultural evolution sometimes built a fit between agents and their environment, but they do not always do so. Why is folk medicine, for example, so much less reliable than folk natural history?
Three Demonstrations and a Funeral
Authors: Korta Kepa , Perry John
Published: March 2006

Abstract:  Gricean pragmatics seems to pose a dilemma. If semantics is limited to the conventional meanings of types of expressions, then the semantics of an utterance does not determine what is said. If all that figures in the determination of what is said counts as semantics, then pragmatic reasoning about the specific intentions of a speaker intrudes on semantics. The dilemma is false. Key points: Semantics need not determine what is said, and the description, with which the hearer begins, need not provide the hearer with knowledge of what was said, or the ability to express what was said, from the hearer's context.
Is Meaning Normative?
Authors: Hattiangadi Anandi
Published: March 2006

Abstract: Many people claim that semantic content is normative, and that therefore naturalistic theories of content face a potentially insuperable difficulty. The normativity of content allegedly undermines naturalism by introducing a gap between semantic ‘ought's and the explanatory resources of naturalism. I argue here that this problem is not ultimately pressing for naturalists. The normativity thesis, I maintain, is ambiguous; it could mean either that the content of a term prescribes a pattern of use, or that it merely determines which pattern of use can be described as ‘correct’. For the anti‐naturalist argument to go forward, content must be prescriptive. I argue, however, that it is not. Moreover, the thesis that content supplies standards for correct use is insufficient to supply a similar, a priori objection to naturalism.
Accelerated growth of intestinal tumours after radiation exposure in Mlh1‐knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC
Authors: Tokairin Yutaka , Kakinuma Shizuko , Arai Masami , Nishimura Mayumi , Okamoto Mieko , Ito Eisaku , Akashi Makoto , Miki Yoshio , Kawano Tatsuyuki , Iwai Takehisa , Shimada Yoshiya
Published: March 2006

Mlh1‐knockout mice have been developed as a useful model of hereditary non‐polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1–/– mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1–/– mice expressed p53 and showed a lack of transforming growth factor (TGF)‐βRII mutation, which resulted in the expression of TGF‐βRII protein. Irradiation of 10‐week‐old Mlh1–/– mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/– and Mlh1+/+ mice were not susceptible to spontaneous or radiation‐induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1–/– mice suggest that this mouse is a good model for HNPCC, although tumour‐related responsible genes might be different from HNPCC. As X‐ray exposure promoted carcinogenesis of GIT in adult Mlh1–/– mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration.
Deletion mapping of chromosome 13q in head and neck squamous cell carcinoma in Indian patients: correlation with prognosis of the tumour
Authors: Golam Sabbir Md. , Roy Anup , Mandal Syamsundar , Dam Aniruddha , Roychoudhury Susanta , Panda Chinmay Kumar
Published: March 2006

Deletions in chromosome (chr.) 13q occur frequently in head and neck squamous cell carcinoma (HNSCC). Previous studies failed to identify common deleted regions in chr.13q, though several candidate tumour suppressor genes (TSGs) loci, e.g. BRCA2, RB1 and BRCAX have been localized in this chromosome, as well as no prognostic significance of the deletion has been reported. Thus, in the present study, deletion mapping of chr. 13q has been done in 55 primary HNSCC samples of Indian patients using 11 highly polymorphic microsatellite markers of which three were intragenic to BRCA2 gene, one intragenic to RB1 gene and another from BRCAX locus. The deletion in chr.13q was significantly associated with progression of HNSCC. High frequencies (27–39%) of loss of heterozygosity were found in 13q13.1 (BRCA2), 13q14.2 (RB1), 13q21.2–22.1 (BRCAX) and 13q31.1 regions. Deletions in the BRCA2 and RB1 regions were significantly correlated. The four highly deleted regions were associated with clinical stage and histological grades of the tumour as well as poor patient outcome. Deletion in the 13q31.1 region was only found to be associated with HPV infection. High frequencies (11–23%) of microsatellite size alteration (MA) were seen to overlap with the highly deleted regions. Forty per cent of the samples showed rare biallelic alteration whereas loss of normal copy of chromosome 13q was seen in five tumours. Thus, it seems that the putative TSGs located in the BRCAX and 13q31.1 regions as well as the BRCA2 and RB1 genes may have some cumulative effect in progression and poor prognosis of HNSCC. Significant association between deletion in BRCA2 and RB1 gene loci may indicate functional relationship between the genes in this tumour progression.
Development of diabetes in non‐obese diabetic mice promotes Chlamydia pneumoniae dissemination from lung to peripheral blood
Authors: Yamaguchi Hiroyuki , Oshio Ichiro , Osaki Takako , Kurata Satoru , Yamamoto Yoshimasa , Kamiya Shigeru
Published: March 2006

We examined a possible association between development of diabetes in non‐obese diabetic (NOD) mice and dissemination of Chlamydia (Chlamydophila) pneumoniae from lung to peripheral blood. By real‐time reverse transcription‐polymerase chain reaction (RT‐PCR) with primers for C. pneumoniae 16S rRNA, following multiple intranasal inoculations, we detected bacteria in lung in NOD mice with diabetes (38.5%) as well as Institute of Cancer Research, USA (ICR) mice (40%), but prevalence of bacteria in NOD mice without diabetes (pre‐diabetic NOD mice and non‐diabetic retired NOD mice) was very low (4.8%). The bacteria were only detected in peripheral blood mononuclear cells (PBMCs) cultured with hydrocortisone of the NOD mice with diabetes (53.8%). Results of immunostaining with fluorescein isothiocyanate‐conjugated antichlamydia monoclonal antibody also showed the presence of bacterial antigens in the lungs and the PBMCs judged as positive by the RT‐PCR. However, C. pneumoniae from cultured PBMCs of all NOD mice was undetected by cultivation method with inclusion‐forming units assay. In addition, no influence of C. pneumoniae intranasal inoculation on development of diabetes in NOD mice was confirmed. Thus, the development of diabetes in NOD mouse appears to be one of critical factors for promoting the dissemination of C. pneumoniae from lung to peripheral blood.