bluuebunny/crossref_metadata_2025 huggingface dataset:
Center of Excellence for Headache Care: Group Model at Kaiser Permanente
Authors: Blumenfeld Andrew , Tischio Marie
Published: May 2003

Objective.—To evaluate the effectiveness of a disease management model for primary headache by: (1) assessing improvement in patients' quality of life, (2) decreasing headache‐related visits to primary care and emergency departments, and (3) maintaining high levels of patient and physician satisfaction.

Background.—Patients with headache regularly seek health care but, in general, are dissatisfied with the care they receive. Patients with primary headaches utilize resources and cost health plans more than patients with other chronic diseases. Primary care visits are time restricted, prohibiting adequate headache evaluation and management. Practice guidelines are inconsistently followed, and access to headache specialists is limited. This headache management program implemented an alternative means of delivering care to manage large volumes of patients with headache. A multidisciplinary team approach coordinated by a neurologist, utilizing education and a nurse practitioner as the main provider of care, was the central process of the program.

Methods.—This was a pilot study involving a prospective cohort with defined outcome measures. Inclusion criteria were adult patients with primary headaches. Patients initially attended an educational session instructed by a neurologist and a nurse practitioner. The patient was subsequently evaluated by the nurse practitioner who developed and coordinated a comprehensive individual treatment plan. The Migraine‐Specific Quality of Life and the Medical Outcomes Study 36‐Item Short Form Questionnaires were completed at baseline, at follow‐up visits, and 6 months after completion of the program. Subjective patient assessment of improvement in their headaches, chart review for tabulation of headache‐related visits, and primary care physician satisfaction surveys were measured.

Results.—Both the Migraine‐Specific questionnaire and the Short Form‐36 measurements demonstrated a statistically significant improvement at 8 weeks, and this was maintained for 6 months after completing the program. At completion of the program, 92% of patients reported subjective improvement. Patient visits for headaches to primary care and emergency departments showed a significant decrease. High levels of satisfaction for primary care physicians were achieved.

Conclusions.—A disease management model using a multidisciplinary team improved individualized patient care. This model increased patient/provider rapport and communication through an educational class. It empowered the patient to take control of their health care by utilizing shared decision making. Patient satisfaction improved and overall health care utilization was reduced.
Demographic and Migraine Characteristics of Adolescents With Migraine: Glaxo Wellcome Clinical Trials' Database
Authors: Winner P. , Rothner A. D. , Putnam D. G. , Asgharnejad M.
Published: May 2003

Objective.—To describe the demographics and migraine characteristics of patients in the Glaxo Wellcome adolescent clinical trials' database.

Methods.—Data from 8 sumatriptan (tablet and nasal spray) and naratriptan (tablet) trials (6 placebo controlled and 2 open label) were reviewed. Adolescents aged 12 to 17 years who had participated in migraine clinical trials and used at least 1 dose of study medication were summarized using descriptive statistics. Patient demographic (gender, age, race, height, and weight) and migraine (diagnosis, pain location and intensity, time and day of migraine onset and treatment, and associated symptoms) characteristics were examined.

Results.—One thousand nine hundred thirty‐two adolescents with migraine were identified; mean age was 14.1 years (standard deviation, 1.64; range, 11 to 18) and 54% of patients were female. More males were represented in the 12‐ to 14‐year‐old group (646 [73%] of 885) than in the 15‐ to 17‐year‐old group (234 [26%] of 885). Most patients reported migraine without aura (67%, 1121 of 1672), unilateral migraine pain (58%, 458 of 787), and pulsating pain (74%, 582 of 790). Migraine was aggravated by physical activity in most of the adolescents (88%, 526 of 598). Most migraine attacks (73%, 1363 of 1858) began between 6 am and 6 pm, and proportionately more attacks occurred Monday through Wednesday. Pretreatment vomiting was experienced by 5% (97 of 1830) of patients, nausea by 53% (983 of 1849), and photophobia or phonophobia (or both) by 88% (1628 of 1858) of patients. The incidence of associated symptoms was directly related to pretreatment headache severity.

Conclusions.—In this large clinical trials' database, adolescents had migraine without aura characterized by unilateral and pulsating pain and aggravated by activity. The incidence of associated symptoms was directly related to pretreatment pain intensity. More migraines occurred Monday through Wednesday during typical school hours. These data may facilitate clinicians' efforts to tailor migraine therapy to the needs of this patient population.
Cerebrovascular Reactivity in Adolescents With Migraine and Tension‐Type Headache During Headache‐Free Interval and Attack
Authors: Rosengarten Bernhard , Sperner Jürgen , Görgen‐Pauly Ute , Kaps Manfred
Published: May 2003

Background.—Migraine is a common cause of headache in adolescents. Assuming that the cerebral vasculature is involved in the pathophysiology of migraine, we compared cerebral vasoreactivity in adolescents both during a migraine attack and a headache‐free interval.

Methods.—A functional transcranial Doppler test utilizing a visual stimulation paradigm was undertaken to measure the evoked flow velocity in the posterior cerebral artery of adolescents suffering from a migraine without aura or a tension‐type headache. To serve as a control, data previously obtained from age‐matched adolescents with no primary headache disorder were used. The flow curves were evaluated by determining the maximal flow velocity increase and by modeling their time course according to a control system analysis. In that analysis, the main dynamic features of the flow response were described mathematically in terms of a control system model of low order. The parameters were time delay, gain, attenuation, rate time, and natural frequency.

Results.—The attenuation parameter (P<.005), indicative of an increased tone of the vessel, and the resting absolute flow velocity (P<.01) both showed a significant increase during an attack in the adolescents with migraine; the gain parameter showed a trend towards similar increase (P  =  .07). The maximal flow velocity did not increase significantly during an attack.

Conclusions.—The control system approach utilized here appears to be more sensitive for detecting migraine‐associated changes in cerebral vasoreactivity than examination of the maximal flow velocities alone.
Carnitine Palmityltransferase II (CPT2) Deficiency and Migraine Headache: Two Case Reports
Authors: Kabbouche Marielle A. , Powers Scott W. , Vockell Anna‐Liisa B. , LeCates Susan L. , Cfnp  , Hershey Andrew D.
Published: May 2003

Background.—Migraine headache is common and has multiple etiologies. A number of mitochondrial anomalies have been described for migraine, and mitochondrial dysfunction has been implicated as one potential pathophysiological mechanism. Carnitine is used by mitochondria for fatty acid transportation; its deficiency, however, has not been implicated in migraine pathophysiology.

Methods and Results.—Two adolescent girls presented to the Headache Center at Cincinnati Children's Hospital Medical Center with frequent headaches and were diagnosed with migraine by the International Headache Society (IHS) criteria. Both girls had a history of recurrent fatigue, muscle cramps, and multiple side effects from their prophylactic treatment. Carnitine levels were measured and found to be low. Carnitine supplementation was initiated. Both patients had a reduction in headache frequency, as well as an improvement in their associated symptoms and other complaints. A skin and muscle biopsy obtained from one patient revealed a partial carnitine palmityltransferase II deficiency in the muscle only.

Conclusion.—Carnitine palmityltransferase II deficiency may represent another etiology for migraine headache, and may be useful in further defining the pathophysiology of migraine. When properly recognized, supplementation with carnitine may improve the outcome of the migraine as well as the carnitine‐associated symptoms.
Facial Pain as the Presenting Symptom of Lung Carcinoma With Normal Chest Radiograph
Authors: Abraham P. James , Capobianco David J. , Cheshire William P.
Published: May 2003

Facial pain is a rare presenting symptom of nonmetastatic lung carcinoma. Referred pain from tumor invasion and compression of the vagus nerve was the presumed cause in the 31 cases published to date. We report 2 additional cases having an unusual clinical feature, namely, both had radiographic evidence of malignancy absent on initial chest films. Severe facial pain in both cases was explained by pulmonary carcinoma detected only through further investigations. From these cases follows the notable conclusion that referred facial pain of malignant origin can occasionally precede the appearance of neoplasm on routine chest films. It is therefore important for physicians to be familiar with the clinical features of this syndrome in order to choose appropriate further diagnostic testing in patients who may be at risk.
A Prospective Study of the Requirement for and the Provision of Epilepsy Surgery in the United Kingdom
Authors: Lhatoo Samden D. , Solomon Juliet K. , McEvoy Andrew W. , Kitchen Neil D. , Shorvon Simon D. , Sander Josemir W.
Published: May 2003

Summary:  Purpose: Of the 30,000 persons in whom epilepsy develops annually in the United Kingdom, in ∼6000 (20%), intractability develops. Some of these patients will be appropriate for epilepsy surgery. We aimed to estimate the number of patients who should be considered surgical candidates, by extrapolation from a population‐based study of prognosis and the number who are receiving epilepsy surgery, by a survey of U.K. neurosurgeons.

Methods: We identified the number of patients who may eventually require surgery from a prospective cohort of patients with newly diagnosed epilepsy. We identified all U.K. neurosurgeons who had performed any epilepsy surgery in the past year. Each identified surgeon prospectively recorded the number and types of operations carried out for 6 months.

Results: Of newly diagnosed patients each year, 450 (1.5%) may eventually require surgery. Thirty‐two respondents (22% of all U.K. neurosurgeons) reported that they performed epilepsy surgery. The 211 operations were carried out in the 6 months surveyed (422 operations annually or 13 per surgeon per year). Temporal lobe resection (77%) was the most common procedure.

Conclusions: Based on a prevalence of 5/1,000 persons with epilepsy, ≤4,500 patients in the U.K. require epilepsy surgery. Every year, 450 patients with newly diagnosed epilepsy who may eventually require surgery are added to this “surgical pool.” At the current annual rate of operations, a large number of refractory patients remain untreated. This is probably partly because many patients are not referred for specialist care and therefore remain underinvestigated.
Statistical Mapping of Scalp‐Recorded Ictal EEG Records Using Wavelet Analysis
Authors: Battiston John J. , Darcey Terrance M. , Siegel Adrian M. , Williamson Peter D. , Barkan Helen I. , Akay Metin , Thadani Vijay M. , Roberts David W.
Published: May 2003

Summary:  Purpose: The wavelet transform (WT) is well suited for the analysis of signals whose characteristics vary rapidly over time. We devised a computerized method for objective scoring of scalp‐recorded seizures that takes advantage of the WT.

Methods: Using wavelet coefficients as a metric, we devised a statistical scoring method aimed at detecting significant and sustained rhythmic buildup. The approach was used to create spatiotemporal significance maps for each seizure. Each seizure was also independently analyzed by computer and an expert reader not involved in the clinical workup or computer analysis of these patients. Hierarchical decision rules for determining seizure lateralization and localization were established from a training set of seizures and subsequently tested on those from an independent test set of seizures. The test dataset included a total of 57 scalp‐recorded seizures from 18 patients, each with a ≥12‐month seizure‐free surgical outcome.

Results: Validation was determined by the site of surgical resection. Of the 57 seizure records in the test dataset, the computerized approach resulted in 48 correctly lateralized seizures as compared to 34 for the expert reader. Further, the computer correctly localized 41 seizures to the expert's 31.

Conclusions: The method presented appears to provide an objective basis for the intrachannel scoring of ictal EEGs with minimal interference from artifacts and intermittent discharges. Although the approach has so far shown a substantial improvement over expert scoring in estimating the lateralization and locus of seizure onset, further testing is required to fully evaluate fully its diagnostic accuracy.
Surgical Treatment of Multifocal Epilepsy Involving Eloquent Cortex
Authors: Devinsky Orrin , Romanelli Pantaleo , Orbach Darren , Pacia Steven , Doyle Werner
Published: May 2003

Summary:  Purpose: This report describes our long‐term follow‐up for combined resective surgery and multiple subpial transections (MSTs) in patients with refractory epilepsy involving eloquent and noneloquent cortex in multiple lobes. Multiple independent seizure foci made these patients poor candidates for conventional surgery.

Methods: MST and resective surgery were used in 13 patients to treat localization‐related refractory epilepsy involving eloquent and noneloquent cortex of two or more lobes. Preoperative investigation was followed by invasive monitoring.

Results: Eleven patients had MST plus resection involving two different lobes, and two patients had MST plus resection involving three different lobes. MSTs were performed on the primary sensorimotor cortex (eight patients), temporal language area (two patients), Broca's area (one patient), and on both frontal motor and temporal language areas (two patients). Nine patients had a two‐stage procedure, and four patients had a three‐stage procedure (two consecutive subdural grid studies followed by resections). Average follow‐up was 59.2 months (range, 42–98 months). With a modified Engel Outcome Scale, four patients (31%) had a class I outcome; three (23%), class II; three (23%), class III; and three (23%), class IV. Ten (77%) patients had a >50% reduction of seizure burden.

Conclusions: Combined MST and resection can meaningfully improve seizure control in patients with multifocal epilepsy involving eloquent cortex. Prospective randomized studies are needed.
The Influence of Obesity on the Frequency and Distribution of Medication
Authors: Dzien A. , Pfeiffer K. P. , Dzien‐Bischinger Christine , Hoppichler F. , Lechleitner Monika
Published: May 2003

Summary: Obesity is a serious health problem in industrialized countries and is associated with a significant increase in total health care costs. Only few data are available about the costs of drug therapies in patients with an increased body weight treated under clinical routine procedures. Such data could support efforts to intensify obesity prevention and treatment programmes in order to reduce comorbidities and costs.

We have evaluated body mass index (BMI), diagnosis, and medication in 3360 outpatients (2175 women and 1185 men; mean age: 56.7 ± 17.5 years). All patients underwent physical examinations, including BMI determination, and provided a detailed record concerning medication. In 1809 patients, the percentage of body fat content was measured with a bioimpedance method (OMRON BF 302 body fat monitor). Continuous variables were compared using the t‐test or Wilcoxon U‐test. Frequency distributions were compared using chi‐squared tests.

With respect to BMI, most of the patients (n = 1793; 53 %) were overweight or obese, 1349 (40 %) showed a normal BMI and 218 (7 %) a low BMI. The majority of cardiovascular (61 %), rheumatological (61.1 %) and metabolic (60.4 %) medication was administered to overweight and obese patients. Parallel findings could be obtained by analysing the percentage of body fat and the frequency of medication. Overall, 82.5 % of all medication was given to patients with a body fat content >20 %.

Our results support the importance of weight‐reduction programmes in order to prevent an overall increase in the costs of medication as a consequence of overweight and obesity.
Advice Against Smoking is not Effective in Patients with Graves’ Ophthalmopathy
Authors: Karadimas P. , Bouzas E. A. , Mastorakos G.
Published: May 2003

Summary: Advice against smoking is one of the means frequently used in the management of patients with Graves’ ophthalmopathy (GO). The objective of this study was to prospectively evaluate the efficacy of such advice. The study was performed at a referral centre. Eighty‐five smokers out of 102 consecutive patients with GO, who were examined during a 1‐year period, were included in the study. Severity of the disease, smoking history, and the results from a patients’ self‐assessment questionnaire were recorded.

The behavioural intervention consisted in a standardized 2‐min message from the attending ophthalmologist strongly advising each patient to quit. The main outcome measure was smoking cessation during the 1‐year follow‐up period. None of the 85 smokers reported smoking cessation either during the follow‐up visits or at the end point of the study.

The results of our study show that advice against smoking is not effective among patients with GO. Specifically designed intervention programmes may be necessary and should be evaluated in a controlled trial.
Bioavailability of phyto-oestrogens
Authors: Rowland Ian , Faughnan Marian , Hoey Leane , Wähälä Kristiina , Williamson Gary , Cassidy Aedin
Published: May 2003

The term phyto-oestrogen encompasses isoflavone compounds, such as genistein and daidzein, found predominantly in soya products and the lignans, such as matairesinol and secoisolariciresinol, found in many fruits, cereals and in flaxseed. There is evidence that they have potential health benefits in man particularly against hormone-dependent diseases such as breast and prostate cancers and osteoporosis. This has led to intense interest in their absorption and biotransformation in man. The metabolism of isoflavones and lignans in animals and man is complex and involves both mammalian and gut microbial processes. Isoflavones are present predominantly as glucosides in most commercially available soya products; there is evidence that they are not absorbed in this form and that their bioavailability requires initial hydrolysis of the sugar moiety by intestinal β-glucosidases. After absorption, phyto-oestrogens are reconjugated predominantly to glucuronic acid and to a lesser degree to sulphuric acid. Only a small portion of the free aglycone has been detected in blood, demonstrating that the rate of conjugation is high. There is extensive further metabolism of isoflavones (to equol and O-desmethylangolensin) and lignans (to enterodiol and enterolactone) by gut bacteria. In human subjects, even those on controlled diets, there is large interindividual variation in the metabolism of isoflavones and lignans, particularly in the production of the gut bacterial metabolite equol (from daidzein). Factors influencing absorption and metabolism of phyto-oestrogens include diet and gut microflora.
Death by a B Cell Superantigen
Authors: Goodyear Carl S. , Silverman Gregg J.
Published: May 2003

Amongst the many ploys used by microbial pathogens to interfere with host immune responses is the production of proteins with the properties of superantigens. These properties enable superantigens to interact with conserved variable region framework subdomains of the antigen receptors of lymphocytes rather than the complementarity determining region involved in the binding of conventional antigens. To understand how a B cell superantigen affects the host immune system, we infused protein A of Staphylococcus aureus (SpA) and followed the fate of peripheral B cells expressing B cell receptors (BCRs) with VH regions capable of binding SpA. Within hours, a sequence of events was initiated in SpA-binding splenic B cells, with rapid down-regulation of BCRs and coreceptors, CD19 and CD21, the induction of an activation phenotype, and limited rounds of proliferation. Apoptosis followed through a process heralded by the dissipation of mitochondrial membrane potential, the induction of the caspase pathway, and DNA fragmentation. After exposure, B cell apoptotic bodies were deposited in the spleen, lymph nodes, and Peyer's patches. Although in vivo apoptosis did not require the Fas death receptor, B cells were protected by interleukin (IL)-4 or CD40L, or overexpression of Bcl-2. These studies define a pathway for BCR-mediated programmed cell death that is VH region targeted by a superantigen.
Deficiencies of GM-CSF and Interferon γ Link Inflammation and Cancer
Authors: Enzler Thomas , Gillessen Silke , Manis John P. , Ferguson David , Fleming James , Alt Frederick W. , Mihm Martin , Dranoff Glenn
Published: May 2003

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-γ attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.
Overlapping Roles of CXCL13, Interleukin 7 Receptor α, and CCR7 Ligands in Lymph Node Development
Authors: Luther Sanjiv A. , Ansel K. Mark , Cyster Jason G.
Published: May 2003

Lymphoid tissue development is associated with local accumulation of CD4+ CD3− IL-7Rαhi hematopoietic cells that deliver lymphotoxin (LT)α1β2 signals to resident stromal cells. Previous studies have established an important role for CXCL13 (BLC) in the development of Peyer's patches (PP) and some peripheral lymph nodes (LNs), but the chemokine requirements for several LN types, including mesenteric LNs, remain undefined. Using CXCL13−/− mice that additionally carry the paucity of LN T cell mutation (plt/plt), we discovered that CCR7 ligands function in peripheral LN development. We also tested for a genetic interaction during LN development between CXCL13 and a cytokine receptor required in PP development, IL-7Rα. Mice deficient for both CXCL13 and IL-7Rα displayed a striking absence of LNs, including mesenteric LNs. These data extend the role of CXCL13 to the development of all LNs and establish a previously unappreciated role for IL-7Rα in this process. Both circulating and LN CD4+ CD3− IL-7Rαhi cells are shown to express LTα1β2 in an IL-7Rα–dependent manner. Furthermore, CXCL13 was found to be sufficient to mediate CD4+ CD3− IL-7Rαhi cell recruitment in vivo to an ectopic site. These findings indicate that CXCL13 and CCR7 ligands promote accumulation of CD4+ CD3− IL-7Rαhi cells, delivering IL-7Rα–dependent LTα1β2 signals critical for LN development.
Enhanced Antitumor Immunity in Mice Deficient in CD69
Authors: Esplugues Enric , Sancho David , Vega-Ramos Javier , Martínez-A Carlos , Syrbe Uta , Hamann Alf , Engel Pablo , Sánchez-Madrid Francisco , Lauzurica Pilar
Published: May 2003

We investigated the in vivo role of CD69 by analyzing the susceptibility of CD69−/− mice to tumors. CD69−/− mice challenged with MHC class I− tumors (RMA-S and RM-1) showed greatly reduced tumor growth and prolonged survival compared with wild-type (WT) mice. The enhanced anti–tumor response was NK cell and T lymphocyte–mediated, and was due, at least in part, to an increase in local lymphocytes. Resistance of CD69−/− mice to MHC class I− tumor growth was also associated with increased production of the chemokine MCP-1, diminished TGF-β production, and decreased lymphocyte apoptosis. Moreover, the in vivo blockade of TGF-β in WT mice resulted in enhanced anti–tumor response. In addition, CD69 engagement induced NK and T cell production of TGF-β, directly linking CD69 signaling to TGF-β regulation. Furthermore, anti-CD69 antibody treatment in WT mice induced a specific down-regulation in CD69 expression that resulted in augmented anti–tumor response. These data unmask a novel role for CD69 as a negative regulator of anti–tumor responses and show the possibility of a novel approach for the therapy of tumors.
Myelin Oligodendrocyte Glycoprotein–specific T Cell Receptor Transgenic Mice Develop Spontaneous Autoimmune Optic Neuritis
Authors: Bettelli Estelle , Pagany Maria , Weiner Howard L. , Linington Christopher , Sobel Raymond A. , Kuchroo Vijay K.
Published: May 2003

Multiple sclerosis (MS) is considered to be an autoimmune disease of the central nervous system (CNS) that in many patients first presents clinically as optic neuritis. The relationship of optic neuritis to MS is not well understood. We have generated novel T cell receptor (TCR) transgenic mice specific for myelin oligodendrocyte glycoprotein (MOG). MOG-specific transgenic T cells are not deleted nor tolerized and are functionally competent. A large proportion (>30%) of MOG-specific TCR transgenic mice spontaneously develop isolated optic neuritis without any clinical nor histological evidence of experimental autoimmune encephalomyelitis (EAE). Optic neuritis without EAE could also be induced in these mice by sensitization with suboptimal doses of MOG. The predilection of these mice to develop optic neuritis is associated with higher expression of MOG in the optic nerve than in the spinal cord. These results demonstrate that clinical manifestations of CNS autoimmune disease will vary depending on the identity of the target autoantigen and that MOG-specific T cell responses are involved in the genesis of isolated optic neuritis.
Molecular Modeling and Functional Mapping of B7-H1 and B7-DC Uncouple Costimulatory Function from PD-1 Interaction
Authors: Wang Shengdian , Bajorath Jürgen , Flies Dallas B. , Dong Haidong , Honjo Tasuku , Chen Lieping
Published: May 2003

B7-H1 and B7-DC are ligands for PD-1, a receptor implicated in negative regulation of T and B cell functions. These ligands, however, also costimulate T cell responses. It remains elusive whether or not costimulation is mediated through PD-1. By comparative molecular modeling and site-directed mutagenesis, we found that nonconserved residues between these ligands on the A′GFCC′C′′ face mediate interaction with PD-1. This indicates significant structural heterogeneity of the interactions between PD-1 and its ligands. Importantly, ligand mutants with abolished PD-1 binding capacity could still costimulate proliferation and cytokine production of T cells from normal and PD-1–deficient mice. Our results reveal unique binding characteristics of B7-H1 and B7-DC and provide direct evidence for an independent costimulatory receptor other than PD-1.
Ectopic LTαβ Directs Lymphoid Organ Neogenesis with Concomitant Expression of Peripheral Node Addressin and a HEV-restricted Sulfotransferase
Authors: Drayton Danielle L. , Ying Xiaoyan , Lee Jason , Lesslauer Werner , Ruddle Nancy H.
Published: May 2003

Lymph node (LN) function depends on T and B cell compartmentalization, antigen presenting cells, and high endothelial venules (HEVs) expressing mucosal addressin cell adhesion molecule (MAdCAM-1) and peripheral node addressin (PNAd), ligands for naive cell entrance into LNs. Luminal PNAd expression requires a HEV-restricted sulfotransferase (HEC-6ST). To investigate LTαβ's activities in lymphoid organogenesis, mice simultaneously expressing LTα and LTβ under rat insulin promoter II (RIP) control were compared with RIPLTα mice in a model of lymphoid neogenesis and with LTβ−/− mice. RIPLTαβ pancreata exhibited massive intra-islet mononuclear infiltrates that differed from the more sparse peri-islet cell accumulations in RIPLTα pancreata: separation into T and B cell areas was more distinct with prominent FDC networks, expression of lymphoid chemokines (CCL21, CCL19, and CXCL13) was more intense, and L-selectin+ cells were more frequent. In contrast to the predominant abluminal PNAd pattern of HEV in LTβ−/− MLN and RIPLTα pancreatic infiltrates, PNAd was expressed at the luminal and abluminal aspects of HEV in wild-type LN and in RIPLTαβ pancreata, coincident with HEC-6ST. These data highlight distinct roles of LTα and LTαβ in lymphoid organogenesis supporting the notion that HEC-6ST–dependent luminal PNAd is under regulation by LTαβ.
Collaborative Induction of Inflammatory Responses by Dectin-1 and Toll-like Receptor 2
Authors: Gantner Benjamin N. , Simmons Randi M. , Canavera Scott J. , Akira Shizuo , Underhill David M.
Published: May 2003

Toll-like receptors (TLRs) mediate recognition of a wide range of microbial products including lipopolysaccharides, lipoproteins, flagellin, and bacterial DNA, and signaling through TLRs leads to the production of inflammatory mediators. In addition to TLRs, many other surface receptors have been proposed to participate in innate immunity and microbial recognition, and signaling through some of these receptors is likely to cooperate with TLR signaling in defining inflammatory responses. In this report we have examined how dectin-1, a lectin family receptor for β-glucans, collaborates with TLRs in recognizing microbes. Dectin-1, which is expressed at low levels on macrophages and high levels on dendritic cells, contains an immunoreceptor tyrosine-based activation motif–like signaling motif that is tyrosine phosphorylated upon activation. The receptor is recruited to phagosomes containing zymosan particles but not to phagosomes containing immunoglobulin G–opsonized particles. Dectin-1 expression enhances TLR-mediated activation of nuclear factor κB by β-glucan–containing particles, and in macrophages and dendritic cells dectin-1 and TLRs are synergistic in mediating production of cytokines such as interleukin 12 and tumor necrosis factor α. Additionally, dectin-1 triggers production of reactive oxygen species, an inflammatory response that is primed by TLR activation. The data demonstrate that collaborative recognition of distinct microbial components by different classes of innate immune receptors is crucial in orchestrating inflammatory responses.
Dectin-1 Mediates the Biological Effects of β-Glucans
Authors: Brown Gordon D. , Herre Jurgen , Williams David L. , Willment Janet A. , Marshall Andrew S. J. , Gordon Siamon
Published: May 2003

The ability of fungal-derived β-glucan particles to induce leukocyte activation and the production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, is a well characterized phenomenon. Although efforts have been made to understand how these carbohydrate polymers exert their immunomodulatory effects, the receptors involved in generating these responses are unknown. Here we show that Dectin-1 mediates the production of TNF-α in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to the TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF-α in response to fungi, a critical step required for the successful control of these pathogens.
Signal 3 Determines Tolerance versus Full Activation of Naive CD8 T Cells
Authors: Curtsinger Julie M. , Lins Debra C. , Mescher Matthew F.
Published: May 2003

Activation of naive CD8 T cells to undergo clonal expansion and develop effector function requires three signals: (a) Ag, (b) costimulation, and (c) IL-12 or adjuvant. The requirement for the third signal to stimulate Ag-dependent proliferation is variable, making the greatest contribution when Ag levels are low. At high Ag levels, extensive proliferation can occur in vitro or in vivo in the absence of a third signal. However, despite having undergone the same number of divisions, cells that expand in the absence of a third signal fail to develop cytolytic effector function. Thus, proliferation and development of cytolytic function can be fully uncoupled. Furthermore, these cells are rendered functionally tolerant in vivo, in that subsequent restimulation with a potent stimulus results in limited clonal expansion, impaired IFN-γ production, and no cytolytic function. Thus, the presence or absence of the third signal appears to be a critical variable in determining whether stimulation by Ag results in tolerance versus development of effector function and establishment of a responsive memory population.
B Cell–specific Transgenic Expression of Bcl2 Rescues Early B Lymphopoiesis but Not B Cell Responses in BOB.1/OBF.1-deficient Mice
Authors: Brunner Cornelia , Marinkovic Dragan , Klein Jörg , Samardzic Tatjana , Nitschke Lars , Wirth Thomas
Published: May 2003

Mice deficient for the transcriptional coactivator BOB.1/OBF.1 show several defects in B cell differentiation. Numbers of immature transitional B cells in the bone marrow are reduced and fewer B cells reach the periphery. Furthermore, germinal center B cells are absent and marginal zone (MZ) B lymphocytes are markedly reduced. Increased levels of B cell apoptosis in these mice prompted us to analyze expression and function of antiapoptotic proteins. Bcl2 expression is strongly reduced in BOB.1/OBF.1-deficient pre–B cells. When BOB.1/OBF.1-deficient mice were crossed with Bcl2-transgenic mice, B cell development in the bone marrow and numbers of B cells in peripheral lymphoid organs were normalized. However, neither germinal center B cells nor MZ B cells were rescued. Additionally, Bcl2 did not rescue the defects in signaling and affinity maturation found in BOB.1/OBF.1-deficient mice. Interestingly, Bcl2-transgenic mice by themselves show an MZ B cell defect. Virtually no functional MZ B cells were detected in these mice. In contrast, mice deficient for Bcl2 show a relative increase in MZ B cell numbers, indicating a previously undetected function of Bcl2 for this B cell compartment.
Regulation of Fyn Through Translocation of Activated Lck into Lipid Rafts
Authors: Filipp Dominik , Zhang Jenny , Leung Bernadine L. , Shaw Andrey , Levin Steven D. , Veillette André , Julius Michael
Published: May 2003

Whether or how the activation of Lck and Fyn during T cell receptor (TCR) signaling is coordinated, and their delivery of function integrated, is unknown. Here we show that lipid rafts function to segregate Lck and Fyn in T cells before activation. Coaggregation of TCR and CD4 leads to Lck activation within seconds outside lipid rafts, followed by its translocation into lipid rafts and the activation of colocalized Fyn. Genetic evidence demonstrates that Fyn activation is strictly dependent on receptor-induced translocation of Lck. These results characterize the interdependence of Lck and Fyn function and establish the spatial and temporal distinctions of their roles in the cellular activation process.
A Role for Complement in Feedback Enhancement of Antibody Responses by IgG3
Authors: de Ståhl Teresita Díaz , Dahlström Jörgen , Carroll Michael C. , Heyman Birgitta
Published: May 2003

IgG1, IgG2a, and IgG2b, passively administered with soluble Ags, enhance specific Ab responses. The effect of IgG3 in this type of feedback regulation has not been studied previously. We immunized mice with trinitrophenyl (TNP)-coupled carrier proteins (bovine serum albumin [BSA] or ovalbumin [OVA]) alone or complexed to monoclonal TNP-specific IgG3. The carrier-specific Ab responses were enhanced by several hundred-fold by IgG3. Enhancement was significantly impaired in mice depleted of complement factor C3 and in mice lacking complement receptors 1 and 2 (Cr2−/−). In contrast, mice lacking the common Fc-receptor gamma chain (FcRγ−/−), resulting in reduced expression of FcγRI and lack of FcγRIII, and mice lacking FcγRIIB (FcγRIIB−/−), responded equally well to immunization with IgG3-complexed Ag as wild-type controls. These findings demonstrate that IgG3 can induce feedback enhancement and that IgG3, in analogy with IgM, uses the complement system for this function.
Cooperating Mechanisms of CXCR5 and CCR7 in Development and Organization of Secondary Lymphoid Organs
Authors: Ohl Lars , Henning Golo , Krautwald Stefan , Lipp Martin , Hardtke Svenja , Bernhardt Günter , Pabst Oliver , Förster Reinhold
Published: May 2003

Homeostatic chemokines participate in the development of secondary lymphoid organs and later on in the functional organization of these tissues. The development of lymph nodes (LNs) and Peyer's patches depends on the recruitment of CD3− CD4+ interleukin (IL)-7Rαhi cells to sites of future organ development. CD3− CD4+ IL-7Rαhi cells express the chemokine receptor CXCR5 and might be attracted by its ligand CXCL13, which is secreted by mesenchymal cells. Mesenchymal cells also secrete CCL19, a ligand for CCR7, yet it is not clear whether CCR7 and CCL19 are important for secondary lymphoid organ development. Analyzing CXCR5−/− CCR7−/− double deficient mice we now show that these mice lack all examined peripheral LNs suggesting a profound role for both receptors in secondary lymphoid organ development. We demonstrate that CD3− CD4+ IL-7Rαhi cells express CXCR5 as well as CCR7 indicating that both receptors cooperate during an early step of secondary lymphoid organ development. Furthermore, CXCR5−/− CCR7−/− mice display a severely disturbed architecture of mesenteric LN and spleen. Due to an impaired migration of B cells into the white pulp, CXCR5−/− CCR7−/− mice fail to develop B cell follicles but show small clusters of unorganized lymphocytes in the spleen. These data demonstrate a cooperative function of CXCR5 and CCR7 in lymphoid organ organogenesis and organization.
Constitutive Expression of AID Leads to Tumorigenesis
Authors: Okazaki Il-mi , Hiai Hiroshi , Kakazu Naoki , Yamada Shuichi , Muramatsu Masamichi , Kinoshita Kazuo , Honjo Tasuku
Published: May 2003

Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy.
Expression of a Targeted λ1 Light Chain Gene Is Developmentally Regulated and Independent of Igκ Rearrangements
Authors: Oberdoerffer Philipp , Novobrantseva Tatiana I. , Rajewsky Klaus
Published: May 2003

Immunoglobulin light chain (IgL) rearrangements occur more frequently at Igκ than at Igλ. Previous results suggested that the unrearranged Igκ locus negatively regulates Igλ transcription and/or rearrangement. Here, we demonstrate that expression of a VJλ1-joint inserted into its physiological position in the Igλ locus is independent of Igκ rearrangements. Expression of the inserted VJλ1 gene segment is developmentally controlled like that of a VJκ-joint inserted into the Igκ locus and furthermore coincides developmentally with the occurrence of Igκ rearrangements in wild-type mice. We conclude that developmentally controlled transcription of a gene rearrangement in the Igλ locus occurs in the presence of an unrearranged Igκ locus and is therefore not negatively regulated by the latter. Our data also indicate light chain editing in ∼30% of λ1 expressing B cell progenitors.
Counterexamples to the 0-1 Conjecture
Authors: McLarnan Timothy , Warrington Gregory
Published: May 2003

For permutations

x
x

and

w
w

, let

μ
(
x
,
w
)

\mu (x,w)

be the coefficient of highest possible degree in the Kazhdan-Lusztig polynomial

P

x
,
w

P_{x,w}

. It is well-known that the

μ
(
x
,
w
)

\mu (x,w)

arise as the edge labels of certain graphs encoding the representations of

S
n

S_n

. The 0-1 Conjecture states that the

μ
(
x
,
w
)
∈
{
0
,
1
}

\mu (x,w) \in \{0,1\}

. We present two counterexamples to this conjecture, the first in

S

16

S_{16}

, for which

x
x

and

w
w

are in the same left cell, and the second in

S

10

S_{10}

. The proof of the counterexample in

S

16

S_{16}

relies on computer calculations.
TheSaccharomyces cerevisiaeSpindle Pole Body Is a Dynamic Structure
Authors: Yoder Tennessee J. , Pearson Chad G. , Bloom Kerry , Davis Trisha N.
Published: May 2003

During spindle pole body (SPB) duplication, the new SPB is assembled at a distinct site adjacent to the old SPB. Using quantitative fluorescence methods, we studied the assembly and dynamics of the core structural SPB component Spc110p. The SPB core exhibits both exchange and growth in a cell cycle-dependent manner. During G1/S phase, the old SPB exchanges ∼50% of old Spc110p for new Spc110p. In G2 little Spc110p is exchangeable. Thus, Spc110p is dynamic during G1/S and becomes stable during G2. The SPB incorporates additional Spc110p in late G2 and M phases; this growth is followed by reduction in the next G1. Spc110p addition to the SPBs (growth) also occurs in response to G2 and mitotic arrests but not during a G1 arrest. Our results reveal several dynamic features of the SPB core: cell cycle-dependent growth and reduction, growth in response to cell cycle arrests, and exchange of Spc110p during SPB duplication. Moreover, rather than being considered a conservative or dispersive process, the assembly of Spc110p into the SPB is more readily considered in terms of growth and exchange.
Inhibition of a Golgi Complex Lysophospholipid Acyltransferase Induces Membrane Tubule Formation and Retrograde Trafficking
Authors: Drecktrah Daniel , Chambers Kimberly , Racoosin Esther L. , Cluett Edward B. , Gucwa Amy , Jackson Brian , Brown William J.
Published: May 2003

Recent studies have suggested that formation of Golgi membrane tubules involves the generation of membrane-associated lysophospholipids by a cytoplasmic Ca2+-independent phospholipase A2(PLA2). Herein, we provide additional support for this idea by showing that inhibition of lysophospholipid reacylation by a novel Golgi-associated lysophosphatidylcholine acyltransferase (LPAT) induces the rapid tubulation of Golgi membranes, leading in their retrograde movement to the endoplasmic reticulum. Inhibition of the Golgi LPAT was achieved by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976), a previously characterized antagonist of acyl-CoA cholesterol acyltransferase. The effect of CI-976 was similar to that of brefeldin A, except that the coatomer subunit β-COP remained on Golgi-derived membrane tubules. CI-976 also enhanced the cytosol-dependent formation of tubules from Golgi complexes in vitro and increased the levels of lysophosphatidylcholine in Golgi membranes. Moreover, preincubation of cells with PLA2antagonists inhibited the ability of CI-976 to induce tubules. These results suggest that Golgi membrane tubule formation can result from increasing the content of lysophospholipids in membranes, either by stimulation of a PLA2or by inhibition of an LPAT. These two opposing enzyme activities may help to coordinately regulate Golgi membrane shape and tubule formation.
Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4
Authors: Venkatesan Sundararajan , Rose Jeremy J. , Lodge Robert , Murphy Philip M. , Foley John F.
Published: May 2003

Desensitization of the chemokine receptors, a large class of G protein–coupled receptors, is mediated in part by agonist-driven receptor endocytosis. However, the exact pathways have not been fully defined. Here we demonstrate that the rate of ligand-induced endocytosis of CCR5 in leukocytes and expression systems is significantly slower than that of CXCR4 and requires prolonged agonist treatment, suggesting that these two receptors use distinct mechanisms. We show that the C-terminal domain of CCR5 is the determinant of its slow endocytosis phenotype. When the C-tail of CXCR4 was exchanged for that of CCR5, the resulting CXCR4-CCR5 (X4-R5) chimera displayed a CCR5-like trafficking phenotype. We found that the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts. CXCR4 and a C-terminally truncated CCR5 mutant (CCR5-KRFX) lacking these cysteines are not raft associated and are endocytosed by a clathrin-dependent pathway. Genetic inhibition of clathrin-mediated endocytosis demonstrated that a significant fraction of ligand-occupied CCR5 trafficked by clathrin-independent routes into caveolin-containing vesicular structures. Thus, the palmitoylated C-tail of CCR5 is the major determinant of its raft association and endocytic itineraries, differentiating it from CXCR4 and other chemokine receptors. This novel feature of CCR5 may modulate its signaling potential and could explain its preferential use by HIV for person-to-person transmission of disease.
Sudden Telomere Lengthening Triggers a Rad53-dependent Checkpoint inSaccharomyces cerevisiae
Authors: Viscardi Valeria , Baroni Enrico , Romano Michele , Lucchini Giovanna , Longhese Maria Pia
Published: May 2003

Telomeres are specialized functional complexes that ensure chromosome stability by protecting chromosome ends from fusions and degradation and avoiding chromosomal termini from being sensed as DNA breaks. Budding yeast Tel1 is required both for telomere metabolism and for a Rad53-dependent checkpoint responding to unprocessed double-strand breaks. We show that overexpression of a GAL1-TEL1 fusion causes transient telomere lengthening and activation of a Rad53-dependent G2/M checkpoint in cells whose telomeres are short due to the lack of either Tel1 or Yku70. Sudden telomere elongation and checkpoint-mediated cell cycle arrest are also triggered in wild-type cells by overproducing a protein fusion between the telomeric binding protein Cdc13 and the telomerase-associated protein Est1. Checkpoint activation by GAL1-TEL1 requires ongoing telomere elongation. In fact, it is turned off concomitantly with telomeres reaching a new stable length and is partially suppressed by deletion of the telomerase EST2 gene. Moreover, both telomere length rebalancing and checkpoint inactivation under galactose-induced conditions are accelerated by high levels of either the Sae2 protein, involved in double-strand breaks processing, or the negative telomere length regulator Rif2. These data suggest that sudden telomere lengthening elicits a checkpoint response that inhibits the G2/M transition.