bluuebunny/crossref_metadata_2025 huggingface dataset:
Air pollution and chest diseases - a review
Authors: Ali Taskina , Hossain Md Ali , Bennoor Kazi Saifuddin
Published: October 2009

Ambient (outdoor) air pollution is now recognized as an important problem, both nationally and worldwide. Our scientific understanding of the spectrum of health effects of air pollution has increased, and numerous studies are discovering important health effects from air pollution at levels once considered safe. Elderly, children and infants are among the most susceptible to many of the air pollutants. In addition to associations between air pollution and respiratory symptoms, asthma exacerbations, and asthma hospitalizations, recent studies have found links between air pollution and preterm birth, infant mortality, deficits in lung growth, and possibly, development of asthma. This paper summarizes the recent literature linking ambient air pollution to adverse health outcomes in population and includes a perspective on the current regulatory process. The review provides advice to pediatricians on how to integrate issues regarding air quality and health into patient education and patients' environmental health advocacy and concludes with recommendations to the government on promotion of effective air-pollution policies to ensure protection of our health.   DOI: 10.3329/bjpp.v22i1.3566 Bangladesh J Physiol Pharmacol 2006; 22(1/2) : 25-28
Substituted N-Phenylpyrazine-2-carboxamides: Synthesis and Antimycobacterial Evaluation
Authors: Doležal Martin , Zitko Jan , Kešetovičová Diana , Kuneš Jiří , Svobodová Michaela
Published: October 2009

The condensation of chlorides of substituted pyrazinecarboxylic acids with ringsubstituted anilines yielded twelve substituted pyrazinecarboxylic acid amides. The synthetic approach, analytical, and lipophilicity data of the newly synthesized compounds are presented. Two antituberculosis assays were used. Firstly, the antimycobacterial activity against four different Mycobacterium strains in a series of pyrazine derivatives was investigated. Secondly, the antimycobacterial evaluation was performed at the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) program. Interesting in vitro antimycobacterial activity was found, N-(3-iodo-4-methylphenyl) pyrazine-2-carboxamide (9) was most active derivative compound against M. tuberculosis (MIC < 2.0 μmol/L), while another iodo derivative 5-tert-butyl-6-chloro-N-(3-iodo-4-methyl-phenyl)pyrazine-2-carboxamide (12) was the most active compound in the TAACF antituberculosis screening program (IC90 = 0.819 μg/mL).
New Flavonoid Glycosides from Elsholtzia rugulosa Hemsl.
Authors: She Gaimei , Guo Zhiqin , Lv Haining , She Dongmei
Published: October 2009

Elsholtzia rugulosa Hemsl. is known in China as a local herbal tea, medicinal herb and honey plant. Chemical examination of E. rugulosa led to the isolation of two new flavonoid glycosides, apigenin 4'-O-α-D-glucopyranoside (1) and 5,7,3',4'-tetrahydroxy-5'-C-prenylflavone-7-O-β-D-glucopyranoside (2), together with nine known flavonoids. Their structures were elucidated on the basis of spectroscopic evidence.
Fluorescence Enhancement of Fluorescein Isothiocyanate-Labeled Protein A Caused by Affinity Binding with Immunoglobulin G in Bovine Plasma
Authors: Ogawa Takehito , Aoyagi Satoka , Miyasaka Takehiro , Sakai Kiyotaka
Published: October 2009

Fluorescence enhancement of fluorescein isothiocyanate-labeled protein A (FITC-protein A) caused by the binding with immunoglobulin G (IgG) in bovine plasma was studied. FITC-protein A was immobilized onto a glass surface by covalent bonds. An increase in fluorescence intensity was dependent on IgG concentration ranging from 20 to 78 μg/mL in both phosphate buffer saline and bovine plasma. This method requires no separation procedure, and the reaction time is less than 15 min. A fluorescence enhancement assay by the affinity binding of fluorescence-labeled reagent is thus available for the rapid determination of biomolecules in plasma.
Cross-Layer Active Predictive Congestion Control Protocol for Wireless Sensor Networks
Authors: Wan Jiangwen , Xu Xiaofeng , Feng Renjian , Wu Yinfeng
Published: October 2009

In wireless sensor networks (WSNs), there are numerous factors that may cause network congestion problems, such as the many-to-one communication modes, mutual interference of wireless links, dynamic changes of network topology and the memory-restrained characteristics of nodes. All these factors result in a network being more vulnerable to congestion. In this paper, a cross-layer active predictive congestion control scheme (CL-APCC) for improving the performance of networks is proposed. Queuing theory is applied in the CL-APCC to analyze data flows of a single-node according to its memory status, combined with the analysis of the average occupied memory size of local networks. It also analyzes the current data change trends of local networks to forecast and actively adjust the sending rate of the node in the next period. In order to ensure the fairness and timeliness of the network, the IEEE 802.11 protocol is revised based on waiting time, the number of the node‟s neighbors and the original priority of data packets, which dynamically adjusts the sending priority of the node. The performance of CL-APCC, which is evaluated by extensive simulation experiments. is more efficient in solving the congestion in WSNs. Furthermore, it is clear that the proposed scheme has an outstanding advantage in terms of improving the fairness and lifetime of networks.
Validation of the Revised Volunteer Motivations Scale for International Sporting Events (VMS-ISE) at the Athens 2004 Olympic Games
Authors: Bang Hyejin , Alexandris Konstantinos , Ross Stephen D.
Published: October 2009

The purpose of the study was to validate the revised Volunteer Motivations Scale for International Sporting Events (VMS-ISE) and to identify subgroup differences in the motives for volunteering using a volunteer sample from the Athens 2004 Olympic Games. Two hundred and six volunteers
(144 males and 62 females) for the Athens 2004 Olympic Games participated in the study and completed the 29-item scale. Results of the confirmatory factor analysis (CFA) provided support for the applicability of the volunteers' motivation questionnaire in the context of the Olympic Games,
with the addition of the Love of Sport factor. The results of both validity (convergent and discriminant) and reliability (internal consistency) analyses were satisfactory. Results also indicated that gender and marital status had a significant effect on specific motivational dimensions.
These findings suggest that the revised VMS-ISE can be a useful tool in measuring volunteer motives in international sporting events, as well as provide a better understanding of subgroup differences on volunteer motivation.
An Impact Evaluation Framework: Local Government Community Festivals
Authors: Wood Emma H.
Published: October 2009

This article brings together the author's previous research and consultancy along with a review of literature from several disciplines to develop a framework that summarizes the concepts, methods, and processes required to successfully evaluate the impacts of local government community
festivals. Events and festivals are a relatively underresearched area but have experienced a growing amount of public sector expenditure. The framework developed and presented here is in response to the need to encourage greater evaluation of this activity and in doing so recognize the complexity
of the process. The impacts of many such festivals are diverse (economic, social, environmental), far reaching (local, national, international), and long term. The evaluation of these impacts, therefore, requires an understanding of the concepts involved and the development of a range of tools
and methods. The proposed framework is informed by the empirical research, theory, and practice in the areas of information systems, marketing communications, event studies, and public sector evaluation. Bringing together these distinct but related fields of study has enabled the development
of a comprehensive and novel approach to event impact evaluation.
A Preliminary Analysis of the Market for Small, Medium, and Large Horticultural Shows in England
Authors: Fox Dorothy , Edwards Jonathan
Published: October 2009

Understanding the consumer is important in estimating the market for an event. This study analyzed the socio-demographic and other characteristics of actual and potential visitors to three styles of English horticultural shows. The shows selected varied in terms of their status (national,
regional, local), the number of visitors they attract, and the length of time they are open to the public. The analysis of the findings of a survey of residents in southern England suggests that while age is a key demographic variable, a more valuable means of segmenting the population is
by their level of enthusiasm for gardening. Furthermore, it is proposed that demand for the largest shows, held nationally, can be established not only through these factors but also by the potential visitors' history of attending smaller horticultural shows. The implications for the marketing
of these and similar events are discussed.
Juvenile Psoriatic Arthritis: Longterm Outcome and Differentiation from Other Subtypes of Juvenile Idiopathic Arthritis
Authors: FLATØ BERIT , LIEN GUNNHILD , SMERDEL-RAMOYA ANNA , VINJE ODD
Published: October 2009

Objective.

To compare outcomes in patients with juvenile psoriatic arthritis (PsA) with those in patients with other juvenile idiopathic arthritis (JIA) subtypes, and to evaluate characteristics and genetic markers that may differentiate PsA from other subtypes of JIA.

Methods.

JIA patients first admitted between 1980 and 1985 were clinically examined after a median of 15 years. Health status was reassessed by the Short Form-36 Health Survey (SF-36) after a median of 23 years. Of 336 JIA patients, 31 (9%) had PsA.

Results.

Predictors of PsA were psoriasis in the patient (OR 12.06, p = 0.004) or first-degree relative (OR 30.86, p < 0.001), dactylitis (OR 10.97, p < 0.001), and ankle/toe arthritis (OR 3.04, p = 0.038) within the first 6 months. HLA-DRB1*11/12 status (OR 2.69, p = 0.040) and onset after age 6 years (OR 4.41, p = 0.004) differentiated PsA from either oligoarthritis or polyarthritis. After 15 years, PsA patients had poorer physical health than healthy population controls (p = 0.001). After 23 years, the SF-36 physical scores were poorer in PsA patients than in those with either oligoarthritis or polyarthritis (p < 0.045). The need for disease-modifying antirheumatic drugs and/or anti-tumor necrosis factor agents was present in 33% of PsA versus 8% in oligoarthritis and 13% in either oligoarthritis or polyarthritis patients (p < 0.001 and p = 0.002, respectively).

Conclusion.

In addition to a history of psoriasis, dactylitis, ankle or toe arthritis, and DRB1*11/12 in children with JIA indicate the likelihood of PsA, a subtype associated with unfavorable outcome.
A Safety Assessment of Tumor Necrosis Factor Antagonists During Pregnancy: A Review of the Food and Drug Administration Database
Authors: CARTER JOHN D. , LADHANI ANIL , RICCA LOUIS R. , VALERIANO JOANNE , VASEY FRANK B.
Published: October 2009

Objective.

To present any congenital anomalies with respect to tumor necrosis factor (TNF) antagonists reported to the US Food and Drug Administration (FDA) to determine if there are common findings.

Methods.

A review of the FDA database of reported adverse events with etanercept, infliximab, and adalimumab from 1999 through December of 2005 was performed. Key words for congenital anomalies were employed as search tools. Duplicate reports were eliminated. Any concomitant medicines were recorded.

Results.

Our review of > 120,000 adverse events revealed a total of 61 congenital anomalies in 41 children born to mothers taking a TNF antagonist. Of these mothers, 22 took etanercept and 19 took infliximab. There were no reports in women taking adalimumab. The most common reported congenital anomaly was some form of heart defect. Twenty-four of the 41 (59%) children had one or more congenital anomalies that are part of vertebral abnormalities, anal atresia, cardiac defect, tracheoesophageal, renal, and limp abnormalities (VACTERL) association. There were 34 specific types of congenital anomalies in total, and 19 (56%) of those are part of the VACTERL spectrum. Nine of these 19 (47%) types of VACTERL anomalies were observed statistically significantly more than historical controls (p < 0.01); in 4 of these 9 the p value was ≤ 0.0001. Thirteen (32%) of the children had more than one congenital anomaly; 7 of these 13 children had 2 defects that are part of the VACTERL spectrum. However, only 1 child was diagnosed with VACTERL. In 24/41 cases (59%) the mother was taking no other concomitant medications.

Conclusion.

A seemingly high number of congenital anomalies that are part of the VACTERL spectrum have been reported. These congenital anomalies are occurring at a rate higher than historical controls. This commonality raises concerns of a possible causative effect of the TNF antagonists.
Achievement of a State of Inactive Disease at Least Once in the First 5 Years Predicts Better Outcome of Patients with Polyarticular Juvenile Idiopathic Arthritis
Authors: MAGNANI ALESSANDRA , PISTORIO ANGELA , MAGNI-MANZONI SILVIA , FALCONE ALESSANDRA , LOMBARDINI GIUSEPPINA , BANDEIRA MARCIA , ROSSI FEDERICA , SALA ILARIA , MARTINI ALBERTO , RAVELLI ANGELO
Published: October 2009

Objective.

To investigate whether the achievement of inactive disease in the first 5 years predicts a more favorable outcome of children with juvenile idiopathic arthritis (JIA).

Methods.

We reviewed clinical charts of 123 patients who started taking methotrexate, were followed for at least 5 years, and received a yearly assessment in the first 5 years. At each yearly visit, the presence of inactive disease was assessed. Patients were divided into 3 groups: (1) patients who never reached inactive disease; (2) patients who reached inactive disease in only 1 visit; and (3) patients who reached inactive disease in ≥ 2 visits. Outcome was evaluated after 6 to 18 years (median 7.1 yrs) by assessing the following clinical measures: restricted joint count, Childhood Health Assessment Questionnaire (CHAQ), Juvenile Arthritis Damage Index (JADI), and Poznanski score of radiographic damage.

Results.

In the first 5 years, 62 patients (50.4%) were noted to have active disease at their yearly visit, 40 patients (32.5%) were noted to have inactive disease only once, and 21 patients (17.1%) were noted to have inactive disease in ≥ 2 visits. Patients who achieved inactive disease 1 or more times had lower restricted joint count (p = 0.007) and JADI-Articular score (p = 0.004) at last followup visit than those who never reached such a state. A similar trend, although not significant, was observed for CHAQ and Poznanski score of radiographic damage.

Conclusion.

Attainment of the state of inactive disease at least once in the first 5 years was found to be associated with less longterm joint damage and with a trend toward less functional impairment.
The Influence of the 1997 Updated Classification Criteria for Systemic Lupus Erythematosus: Epidemiology, Disease Presentation, and Patient Management
Authors: EILERTSEN GRO ØSTLI , BECKER-MEROK ANDREA , NOSSENT JOHANNES C.
Published: October 2009

Objective.

The 1997 update of the American College of Rheumatology classification criteria (ACR97) for systemic lupus erythematosus (SLE) has not been validated. We determined to what extent their introduction influenced the epidemiology and clinical characteristics of the disease in northern Norway.

Methods.

Annual incidence and point-prevalence rates, clinical manifestations, and outcome were determined in an inception cohort of patients with SLE in northern Norway, included between 1996 and 2006, using ACR97 criteria (97acr). These findings were compared with a cohort from the same area enrolled 1978–1995 using the 1982 revised criteria ACR82 (82acr).

Results.

The mean annual incidence of SLE was 3.00 for cohort 97acr (n = 58) versus 2.63 for cohort 82acr (n = 81) (p = 0.5). All patients in the 97acr cohort also fulfilled the 1982 criteria; however, significantly fewer patients presented with discoid rash [odds ratio (OR) 0.31)], arthritis (OR 0.24), renal (OR 0.28) or hematological disorder (OR 0.27), and significantly more with anti-dsDNA (OR 2.57) and antiphospholipid antibodies (OR 27.9). Initial treatment with intravenous pulse methylprednisolone (OR 9.23), azathioprine (OR 6.32), and low-dose aspirin (OR 20.9) was increased in cohort 97acr. Five- (95.2%) and 10-year survival (91.9%) rates were also improved for cohort 97acr.

Conclusion.

The ACR97 criteria set has construct validity compared to the ACR82 criteria set. SLE incidence remains unchanged in northern Norway, but a significant reduction of renal disease and further improvements in survival rates occurred simultaneously with increased serological surveillance with ELISA-based assays and early immunosuppressive and anticoagulant therapy.
Metaanalysis of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms Affecting Methotrexate Toxicity
Authors: FISHER MARK C. , CRONSTEIN BRUCE N.
Published: October 2009

Objective.

Methotrexate (MTX) is an effective therapy for rheumatoid arthritis (RA) but it is also associated with toxicity. Pharmacogenetics is the systematic evaluation of the role of genetic differences in the efficacy and toxicity of therapeutic interventions. Because the results of small pharmacogenetic studies are often misleading, we undertook a metaanalysis of published studies to determine the role of polymorphisms in the therapeutic efficacy and toxicity of MTX.

Methods.

A search of PubMed produced 55 publications, which were then reviewed for relevance to MTX toxicity and efficacy in patients with RA. To ensure that no study was missed, each polymorphism found was then entered as an independent search string and all results were reviewed again.

Results.

Only 2 polymorphisms [C677T and A1298C in methylenetetrahydrofolate reductase (MTHFR); total 8 studies] relevant to MTX metabolism and efficacy had sufficient data to allow a metaanalysis of their association with toxicity; there was no polymorphism with sufficient data to perform a metaanalysis of efficacy. In a fixed-effects model, the C677T polymorphism was associated with increased toxicity (OR 1.71, 95% CI 1.32–2.21, p < 0.001). The A1298C polymorphism was not associated with increased toxicity (OR 1.12, 95% CI 0.79–1.6, p = 0.626).

Conclusion.

As pharmacogenetics evolves, more data are needed to assess the role of various polymorphisms for drug efficacy and toxicity. These results illustrate the paucity of reliable pharmacogenetic data on a commonly used antirheumatic drug and the potential role of pharmacogenetics in tailoring drug therapy for an individual patient.
Comparative Performance Analysis of 4 Different Anti-Citrullinated Protein Assays in the Diagnosis of Rheumatoid Arthritis
Authors: MUTLU NILGUN , BICAKCIGIL MUGE , TASAN DEMET A. , KAYA AYHAN , YAVUZ SULE , OZDEN A. INCI
Published: October 2009

Objective.

To evaluate the diagnostic performances of 2 recently developed assays, third-generation anti-cyclic citrullinated peptide (anti-CCP3) and anti-mutated citrullinated vimentin (anti-MCV), in comparison to conventional second-generation anti-cyclic citrullinated peptide (anti-CCP2) assay; and to assess a novel fully automated, random-access AxSYM anti-CCP assay for early diagnosis of rheumatoid arthritis (RA).

Methods.

A cohort of 176 patients was enrolled in our study; 93 were diagnosed as having RA. The non-RA group consisted of 83 patients including 38 with systemic lupus erythematosus, 17 with primary Sjögren’s syndrome, 11 with osteoarthritis, and 17 healthy controls. All were tested for presence of anti-CCP2, anti-CCP3, AxSYM anti-CCP, anti-MCV, and rheumatoid factor (RF)-IgM according to the manufacturers’ instructions.

Results.

Diagnostic performance of the assays revealed the highest area under the curve for the novel AxSYM anti-CCP [89.1; 95% confidence interval (CI) 84.3–93.8], followed by anti-CCP3 (86.7; 95% CI 81.6–91.9), anti-CCP2 (82; 95% CI 75.8–88.3), and anti-MCV (71.9; 95% CI 64.4–79.5). The sensitivities and specificities were 60.2% and 98.8% for anti-CCP2, 61.3% and 97.6% for anti-CCP3, 80.6% and 84.3% for AxSYM anti-CCP, 49.8% and 91.6% for anti-MCV, and 67.8% and 91.6% for RF-IgM, respectively.

Conclusion.

At cutoff of 5 U/ml, AxSYM anti-CCP emerged as a highly sensitive first-line early diagnostic tool for RA, with the greatest discrimination power, above 16 U/ml, in case of positive result. Using a single easily performed automated assay at 2 determined decision limits we were able to diagnose 81% of cases of RA and missing only 1.2%.
Relationship Between Low Bone Mineral Density and Varus Deformity in Postmenopausal Women with Knee Osteoarthritis
Authors: AKAMATSU YASUSHI , MITSUGI NAOTO , TAKI NAOYA , TAKEUCHI RYOHEI , SAITO TOMOYUKI
Published: October 2009

Objective.

To assess the relationship between bone mineral density (BMD) and varus deformity arising from bone structural changes caused by knee osteoarthritis (OA) in postmenopausal women.

Methods.

This cross-sectional study involved 135 consecutive postmenopausal female patients who had varus knee OA and a Kellgren-Lawrence grade ≥ 2. Knee radiographs were obtained with the patient standing on one leg, and subjects were classified into 3 tertile groups according to femorotibial angle, which was taken as a measure of varus knee OA severity. We also measured the 3 subangles that make up the femorotibial angle, and focused on the varus inclination of the tibial plateau. BMD was measured in the lumbar spine, femoral neck, and medial and lateral tibial condyles using dual-energy X-ray absorptiometry. Differences between femorotibial angle tertile groups were assessed, and associations between femorotibial sub-angles and BMD values at various points were evaluated.

Results.

After adjustment for age and body mass index, there was no significant association between the varus inclination of the tibial plateau and lumbar spine BMD. A weak but statistically significant negative correlation existed between varus inclination of the tibial plateau and BMD at the ipsilateral proximal femur and lateral tibial condyle.

Conclusion.

Varus inclination of the tibial plateau was significantly more severe in the femorotibial angle tertile 3 group, and in patients with lower BMD in the ipsilateral lower limb. Varus knee OA may result not only from cartilage loss but also from structural changes of the bone.
The Influence of Sex on Patients with Rheumatoid Arthritis in a Large Observational Cohort
Authors: IIKUNI NORIKO , SATO ERI , HOSHI MASAYA , INOUE EISUKE , TANIGUCHI ATSUO , HARA MASAKO , TOMATSU TAISUKE , KAMATANI NAOYUKI , YAMANAKA HISASHI
Published: October 2009

Objective.

To compare the sex differences of various components of rheumatoid arthritis (RA).

Methods.

Data of 4823 patients from a large observational cohort study were analyzed. Remarkable differences were noted between the sexes, and overall, women had significantly higher disease activity.

Results.

When variables were adjusted using sex, age, and duration, Health Assessment Questionnaire, rather than Disease Activity Score, contributed most to sex difference. Further analysis showed evidence that progression of disability was approximately 3 times more rapid in female patients compared to male patients.

Conclusion.

Women overall have higher RA disease activity and are prone to greater and faster progression of disability over time.
Prednisone, Lupus Activity, and Permanent Organ Damage
Authors: THAMER MAE , HERNÁN MIGUEL A. , ZHANG YI , COTTER DENNIS , PETRI MICHELLE
Published: October 2009

Objective.

To estimate the effect of corticosteroids (prednisone dose) on permanent organ damage among persons with systemic lupus erythematosus (SLE).

Methods.

We identified 525 patients with incident SLE in the Hopkins Lupus Cohort. At each visit, clinical activity indices, laboratory data, and treatment were recorded. The study population was followed from the month after the first visit until June 29, 2006, or attainment of irreversible organ damage, death, loss to follow-up, or receipt of pulse methylprednisolone therapy. We estimated the effect of cumulative average dose of prednisone on organ damage using a marginal structural model to adjust for time-dependent confounding by indication due to SLE disease activity.

Results.

Compared with non-prednisone use, the hazard ratio of organ damage for prednisone was 1.16 (95% CI 0.54, 2.50) for cumulative average doses > 0–180 mg/month, 1.50 (95% CI 0.58, 3.88) for > 180–360 mg/month, 1.64 (95% CI 0.58, 4.69) for > 360–540 mg/month, and 2.51 (95% CI 0.87, 7.27) for > 540 mg/month. In contrast, standard Cox regression models estimated higher hazard ratios at all dose levels.

Conclusion.

Our results suggest that low doses of prednisone do not result in a substantially increased risk of irreversible organ damage.
Antibody Reactivity to α-Enolase in Mothers of Children with Congenital Heart Block
Authors: LLANOS CAROLINA , CHAN EDWARD K.L. , LI SONGQING , ABADAL GRANT X. , IZMIRLY PETER , BYRNE CAROLINE , CLANCY ROBERT M. , BUYON JILL P.
Published: October 2009

Objective.

To evaluate the frequency of anti-α-enolase antibodies in the sera of mothers whose children have congenital heart block (CHB), given provocative results in which α-enolase, a membrane protein, was recognized by monoclonal antibodies reactive with the peptide p200 of 52 kDa Ro/SSA in a neonatal rat heart library.

Methods.

An ELISA using a recombinant α-enolase protein was developed. Sera from 100 anti-Ro52+ CHB mothers in the Research Registry for Neonatal Lupus, 50 patients with systemic lupus erythematosus (SLE; 7 anti-Ro52+), and 48 healthy controls were tested for anti-α-enolase reactivity.

Results.

There were no significant differences in the median values obtained from CHB mothers, patients with SLE, or controls at each of the dilutions tested. Only 7 (7%) at 1:100 dilution and 2 (2%) at 1:1000 dilution of 100 CHB sera were 3 standard deviations above the mean value obtained for controls. Preincubation with recombinant Ro52 did not inhibit anti-α-enolase reactivity.

Conclusion.

The low frequency of anti-α-enolase antibodies in the sera of CHB mothers and the absence of apparent cross-reactivity with Ro52 suggest that antibodies to Ro52 are not likely to mediate CHB via binding to α-enolase.
Cognitive Therapy with Older Adults
Authors: Bienenfeld David
Published: October 2009

CME Educational Objectives

1.

List the conditions for which cognitive therapy is recommended in older adults.

2.

Define the general technical modifications in using cognitive therapy with older patients.

3.

Name particular techniques in implementing cognitive therapy in geriatric depression and anxiety.
A Tribute to Robert Post’s Bipolar ‘Perfect Storm’
Authors: Fawcett Jan
Published: October 2009

This issue of Psychiatric Annals, guest edited by Robert Post, MD, featuring two articles written by him, is mainly focused on the issue of pediatric-onset bipolar disorder. For years, Dr. Post has been trying to draw our attention to the early onset of bipolar disorder and its consequences, articulating the need for more treatment-focused research in bipolar disorder, but particularly child-onset bipolar disorder.
Childhood-Onset Bipolar Disorder: The Perfect Storm
Authors: Post Robert M.
Published: October 2009

A convergence of unfortunate circumstances has generated “the perfect storm” of inadequate treatment of youth with childhood-onset bipolar disorder. Although this condition affects a minority of children, many youth are afflicted and experience long delays in receiving their first treatment. Compared with adult-onset forms of the illness, the childhood-onset form of bipolar disorder carries a poor prognosis throughout adulthood. Yet continued obstacles affect efforts to appropriately identify and treat children. There is only a small amount of treatment-related research yielding several Food and Drug Administration (FDA)-approved medications for children 10 to 19 years. Additionally, there are virtually no medications approved for children with this disorder who are younger than 10 years, despite evidence from various sites suggesting that a sizable number of children experience first symptoms in the earliest years of life.
Common γ-Chain-Dependent Signals Confer Selective Survival of Eosinophils in the Murine Small Intestine
Authors: Carlens Julia , Wahl Benjamin , Ballmaier Matthias , Bulfone-Paus Silvia , Förster Reinhold , Pabst Oliver
Published: October 2009

Eosinophils are potent effector cells that are recruited to sites of inflammation. However, in some tissues, in particular in the gastrointestinal tract, eosinophils constitute an abundant leukocyte population also under homeostatic conditions. The lack of suitable isolation protocols restricted the analysis of these cells to histological assessment of cell numbers while important aspects of their phenotype, turnover, and functions remain unresolved. In this study, we report a protocol that allows the quantitative isolation of intestinal eosinophils. We characterized small intestinal eosinophils by flow cytometry as SSChighCD11b+CD11c+CCR3+Siglec-F+ cells. Intestinal eosinophils resembled eosinophils isolated from thymus and uterus but differed from eosinophils isolated from lung or blood. Eosinophils in intestine, thymus, and uterus showed in vivo a markedly higher life time compared with eosinophils present in lung and blood measured by incorporation of BrdU. This indicates that under steady-state conditions homeostasis of eosinophils is controlled by regulation of cell survival. Intestinal eosinophils are severely reduced in the intestines of Rag-2/common γ-chain double-deficient mice but not Rag-2-deficient mice, correlating with differential expression of GM-CSF and CCL11 in both mouse strains. Moreover, under steady-state conditions, intestinal eosinophils constitutively express high levels of the common γ-chain transcripts compared with lung eosinophils as well as eosinophils present under inflammatory conditions. These observations reveal a hitherto unrecognized diversity in phenotypic and functional properties of eosinophils and suggest that tissue-specific common γ-chain-dependent signals might profoundly affect eosinophil function and homeostasis.
Critical Role of TLR2 and TLR4 in Autoantibody Production and Glomerulonephritis in lpr Mutation-Induced Mouse Lupus
Authors: Lartigue Aurelia , Colliou Natacha , Calbo Sébastien , François Arnault , Jacquot Serge , Arnoult Christophe , Tron Francois , Gilbert Daniele , Musette Philippe
Published: October 2009

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies directed against nuclear Ags and immune complex deposits in damaged organs. Environmental factors have been thought to play a role in the onset of the disease. The recognition of these factors is mediated by TLRs, in particular TLR2 and TLR4 which bind pathogen-associated molecular patterns of Gram+ and Gram− bacteria, respectively. We attempted to determine the role of these TLRs in SLE by creating TLR2- or TLR4-deficient C57BL/6lpr/lpr mice. These mice developed a less severe disease and fewer immunological alterations. Indeed, in C57BL/6lpr/lpr-TLR2 or -TLR4-deficient mice, glomerular IgG deposits and mesangial cell proliferation were dramatically decreased and antinuclear, anti-dsDNA, and anti-cardiolipin autoantibody titers were significantly reduced. However, the response against nucleosome remained unaffected, indicating a role of TLR2 and TLR4 in the production of Abs directed against only certain categories of SLE-related autoantigens. Analysis of B cell phenotype showed a significant reduction of marginal zone B cells, particularly in C57BL/6lpr/lpr-TLR4-deficient mice, suggesting an important role of TLR4 in the sustained activation of these cells likely involved in autoantibody production. Interestingly, the lack of TLR4 also affected the production of cytokines involved in the development of lupus disease.
FROUNT Is a Common Regulator of CCR2 and CCR5 Signaling to Control Directional Migration
Authors: Toda Etsuko , Terashima Yuya , Sato Tsuyoshi , Hirose Kenzo , Kanegasaki Shiro , Matsushima Kouji
Published: October 2009

FROUNT is a known CCR2-binding protein that facilitates monocyte/macrophage infiltration. Here we report that FROUNT also binds to the C-terminal region of CCR5 and enhances CCR5-mediated cellular chemotaxis. We show that FROUNT overexpression enhances the directionality of chemotaxis, while FROUNT suppression results in impaired responsiveness. Furthermore, we found an increase in consolidated pseudopodium formation in FROUNT-overexpressing cells (FNT cells) on uniform stimulation with CCL4 (MIP1-β), a specific ligand of CCR5. In most FNT cells, one to two pseudopodia directed toward higher chemokine concentration were found, whereas most FNT-suppressed cells had multiple pseudopodia. The data indicate that FROUNT is involved in sensing and amplifying a shallow extracellular chemokine gradient that leads to a limited number of accurate pseudopodia directed toward the chemokine concentration. In addition to its separate roles in CCR2- and CCR5-mediated chemotaxis, FROUNT, as a common regulator of these receptors, possibly plays a crucial role in the recruitment of immune cells expressing these receptors.
TNFR2-Deficient Memory CD8 T Cells Provide Superior Protection against Tumor Cell Growth
Authors: Kim Edward Y. , Teh Soo-Jeet , Yang Jocelyn , Chow Michael T. , Teh Hung-Sia
Published: October 2009

TNF receptor-2 (TNFR2) plays a critical role in promoting the activation and survival of naive T cells during the primary response. Interestingly, anti-CD3 plus IL-2 activated TNFR2−/− CD8 T cells are highly resistant to activation-induced cell death (AICD), which correlates with high expression levels of prosurvival molecules such as Bcl-2, survivin, and CD127 (IL-7Rα). We determined whether the resistance of activated TNFR2−/− CD8 T cells to AICD contributes to more effective protection against tumor cell growth. We found that during a primary tumor challenge, despite initial inferiority in controlling tumor cell growth, TNFR2−/− mice were able to more effectively control tumor burden over time compared with wild-type (WT) mice. Furthermore, vaccination of TNFR2−/− mice with recombinant Listeria monocytogenes that express OVA confers better protection against the growth of OVA-expressing E.G7 tumor cells relative to similarly vaccinated WT mice. The enhanced protection against tumor cell growth was not due to more effective activation of OVA-specific memory CD8 T cells in vaccinated TNFR2−/− mice. In vitro studies indicate that optimally activated OVA-specific TNFR2−/− CD8 T cells proliferated to the same extent and possess similar cytotoxicity against E.G7 tumor cells as WT CD8 T cells. However, relative to WT cells, activated OVA-specific TNFR2−/− CD8 T cells were highly resistant to AICD. Thus, the enhanced protection against E.G7 in TNFR2−/− mice is likely due to the recruitment and activation of OVA-specific memory TNFR2−/− CD8 T cells and their prolonged survival at the tumor site.
CCR7-Dependent Stimulation of Survival in Dendritic Cells Involves Inhibition of GSK3β
Authors: Escribano Cristina , Delgado-Martín Cristina , Rodríguez-Fernández José Luis
Published: October 2009

Chemokine receptor CCR7 regulates chemotaxis and survival in mature dendritic cells (DCs). We studied the role of glycogen synthase kinase-3β (GSK3β) in the regulation of CCR7-dependent survival. We show that GSK3β behaves as a proapoptotic regulator in cultured monocyte-derived human DCs and murine splenic DCs in vitro, and in lymph node DCs in vivo. In keeping with its prosurvival role, stimulation of CCR7 induced phosphorylation/inhibition of GSK3β, which was mediated by the prosurvival regulator Akt1, but it was independent of ERK1/2, a key regulator of chemotaxis. Stimulation of CCR7 also induced translocation of two transcription-factor targets of Akt, prosurvival NF-κB and proapoptotic FOXO1, to the nucleus and cytosol, respectively, resulting in DCs with a phenotype more resistant to apoptotic stimuli. We analyzed if GSK3β was able to modulate the mobilizations of these transcription factors. Using pharmacological inhibitors, small interfering RNA, and a construct encoding constitutively active GSK3β, we show that active GSK3β fosters and hampers the translocations to the nucleus of FOXO and NF-κB, respectively. Inhibition of GSK3β resulted in the degradation of the NF-κB inhibitor IκB, indicating a mechanism whereby GSK3 can control the translocation of NF-κB to the nucleus. GSK3β and FOXO interacted in vivo, suggesting that this transcription factor could be a substrate of GSK3. The results provide a novel mechanism whereby active GSK3β contributes to regulate apoptosis in DCs. They also suggest that upon stimulation of CCR7, Akt-mediated phosphorylation/inhibition of GSK3β may be required to allow complete translocations of FOXO and NF-κB that confer DCs an extended survival.
Constitutive Expression of IDO by Dendritic Cells of Mesenteric Lymph Nodes: Functional Involvement of the CTLA-4/B7 and CCL22/CCR4 Interactions
Authors: Onodera Toshiharu , Jang Myoung Ho , Guo Zijin , Yamasaki Mikako , Hirata Takako , Bai Zhongbin , Tsuji Noriko M. , Nagakubo Daisuke , Yoshie Osamu , Sakaguchi Shimon , Takikawa Osamu , Miyasaka Masayuki
Published: October 2009

Dendritic cells (DCs) express the immunoregulatory enzyme IDO in response to certain inflammatory stimuli, but it is unclear whether DCs express this enzyme under steady-state conditions in vivo. In this study, we report that the DCs in mesenteric lymph nodes (MLNs) constitutively express functional IDO, which metabolizes tryptophan to kynurenine. In line with a previous report that regulatory T cells (Tregs) can induce IDO in DCs via the CTLA-4/B7 interaction, a substantial proportion of the MLN DCs were located in juxtaposition to Tregs, whereas this tendency was not observed for splenic DCs, which do not express IDO constitutively. When CTLA-4 was selectively deleted in Tregs, the frequency of IDO-expressing DCs in MLNs decreased significantly, confirming CTLA-4’s role in IDO expression by MLN DCs. We also found that the MLN DCs produced CCL22, which can attract Tregs via CCR4, and that the phagocytosis of autologous apoptotic cells induced CCL22 expression in CCL22 mRNA-negative DCs. Mice genetically deficient in the receptor for CCL22, CCR4, showed markedly reduced IDO expression in MLN-DCs, supporting the involvement of the CCL22/CCR4 axis in IDO induction. Together with our previous observation that MLN DCs contain much intracytoplasmic cellular debris in vivo, these results indicate that reciprocal interactions between the DCs and Tregs via both B7/CTLA-4 and CCL22/CCR4 lead to IDO induction in MLN DCs, which may be initiated and/or augmented by the phagocytosis of autologous apoptotic cells by intestinal DCs. Such a mechanism may help induce the specific milieu in MLNs that is required for the induction of oral tolerance.
Mouse Mast Cell Protease 4 Is the Major Chymase in Murine Airways and Has a Protective Role in Allergic Airway Inflammation
Authors: Waern Ida , Jonasson Sofia , Hjoberg Josephine , Bucht Anders , Åbrink Magnus , Pejler Gunnar , Wernersson Sara
Published: October 2009

It is widely established that mast cells (MCs) have a harmful role in asthma, for example by secreting various proinflammatory substances stored within their secretory granule. However, in this study, we show that one of the substances stored within MC granule, chymase, in fact has a protective role in allergic airway inflammation, indicating that MCs may possess both harmful and protective activities in connection with this type of disease. Wild-type (WT) mice and mice lacking mouse MC protease 4 (mMCP-4), a chymase that is functionally homologous to human chymase, were sensitized and challenged with OVA, followed by the assessment of airway physiology and inflammatory parameters. Our results show that the airway hyperresponsiveness was significantly higher in mMCP-4−/− as compared with WT mice. Moreover, the degree of lung tissue inflammation was markedly higher in mice lacking mMCP-4 than in WT controls. Histological analysis revealed that OVA sensitization/challenge resulted in a marked increased in the thickness of the smooth muscle cell (SMC) layer and, notably, that the degree of SMC layer thickening was more pronounced in mMCP-4−/− animals than in WT controls, thus indicating that chymase may have an effect on airway SMCs. In support of this, mMCP-4-positive MCs were located in the close vicinity of the SMC layer, mainly in the upper airways, and mMCP-4 was shown to be the major chymase expressed in these MCs. Taken together, our results indicate that chymase present in the upper airways protects against allergic airway responses, possibly by regulating SMCs.
Epidermal Langerhans Cells Are Not Required for UV-Induced Immunosuppression
Authors: Wang Liangchun , Jameson Stephen C. , Hogquist Kristin A.
Published: October 2009

UV light can be highly beneficial in the treatment of skin disorders such as psoriasis. It is thought to cause immunosuppression by depleting or altering the function of epidermal Langerhans cells (LC). Our previous studies identified a novel langerin+ dendritic cell in the dermis, distinct from LC in phenotype, circulation, and function. In this study, we determined the role of LC and dermal langerin+ cells in UV suppression. UV light suppressed the CD8 T cell response to both contact hypersensitivity and epicutaneous protein immunization, and resulted in a dramatically altered phenotype of LC. UV light did not alter early CD8 T cell activation in the lymph nodes, but rather reduced CD8 T cell expansion at later time points. We found that dermal langerin+ cells, but not LC, were essential for the CD8 T cell response. Furthermore, in the selective absence of LC, UV light still caused suppression of both CD8 T cell expansion and contact hypersensitivity.
Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses
Authors: Durand Caylib A. , Hartvigsen Karsten , Fogelstrand Linda , Kim Shin , Iritani Sally , Vanhaesebroeck Bart , Witztum Joseph L. , Puri Kamal D. , Gold Michael R.
Published: October 2009

B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the δ isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110δ enzymatic activity, we show that p110δ is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110δ activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110δ activity. Finally, we show that the in vivo production of natural Abs requires p110δ and that p110δ inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110δ may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.
A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity
Authors: Zhao Yangbing , Wang Qiong J. , Yang Shicheng , Kochenderfer James N. , Zheng Zhili , Zhong Xiaosong , Sadelain Michel , Eshhar Zelig , Rosenberg Steven A. , Morgan Richard A.
Published: October 2009

To generate chimeric Ag receptors (CARs) for the adoptive immunotherapy of cancer patients with ErbB2-expressing tumors, a single-chain Ab derived from the humanized mAb 4D5 Herceptin (trastuzumab) was initially linked to T cell signaling domains derived from CD28 and the CD3ζ to generate a CAR against ErbB2. Human PBLs expressing the 4D5 CAR demonstrated Ag-specific activities against ErbB2+ tumors. However, a gradual loss of transgene expression was noted for PBLs transduced with this 4D5 CAR. When the CD3ζ signaling domain of the CAR was truncated or mutated, loss of CAR expression was not observed, suggesting that the CD3ζ signaling caused the transgene decrease, which was supported by the finding that T cells expressing 4D5 CARs with CD3ζ ITAM mutations were less prone to apoptosis. By adding 4-1BB cytoplasmic domains to the CD28-CD3ζ signaling moieties, we found increased transgene persistence in 4D5 CAR-transduced PBLs. Furthermore, constructs with 4-1BB sequences demonstrated increased cytokine secretion and lytic activity in 4D5 CAR-transduced T cells. More importantly, PBLs expressing this new version of the 4D5 CAR could not only efficiently lyse the autologous fresh tumor digests, but they could strongly suppress tumor growth in a xenogenic mouse model.
Thalidomide Inhibits Activation of Caspase-1
Authors: Keller Martin , Sollberger Gabriel , Beer Hans-Dietmar
Published: October 2009

Thalidomide is an efficient anti-inflammatory and anti-angiogenic drug, but its therapeutic use is problematic due to a strong teratogenic activity. Nevertheless, thalidomide was approved for the treatment of inflammatory skin diseases and certain types of cancer, and it is extensively tested for several other indications. Recently, we demonstrated that active caspase-1, whose activation is dependent on inflammasome complexes, is required for unconventional protein secretion of proinflammatory cytokines such as IL-1 and of the proangiogenic fibroblast growth factor 2. In this study, we show that pharmacological doses of thalidomide strongly reduced the secretion of both proteins. Thalidomide-treated cells also released less of other leaderless proteins, which require caspase-1 activity for their secretion. In line with these findings, the drug inhibited activation and activity of caspase-1 in cultured cells but not in vitro. The latter finding suggests that the pharmacological activity is exerted by a metabolite of the drug. The anti-inflammatory activity of thalidomide was also mediated via caspase-1 in mice. These findings represent a novel mechanism by which thalidomide exerts its pharmacological activity and suggest that inhibition of the activity of IL-1 might represent a novel strategy to substitute thalidomide.