bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary arteriovenous fistula in a patient with renal cell carcinoma
Authors: Kopetz S. , Jimenez C. , Tu S-M. , Sharma P.
Published: March 2007

Arteriovenous (AV) fistulas are common in renal cell carcinoma. These are usually small and asymptomatic. Case reports have previously described symptomatic fistulas in primary renal cell tumour or, less commonly, bone metastases.

The current study describes a patient with lung metastases from renal cell carcinoma who developed a symptomatic pulmonary AV fistula. The patient presented with debilitating progressive shortness of breath, which resolved after coiling of the pulmonary AV fistula. Supporting radiographs include a unique ventilation–perfusion finding of perfusion tracer in the kidney that is diagnostic of a pulmonary shunt.

This is the first report of a pulmonary fistula from renal cell carcinoma. This rare complication of renal cell carcinoma reflects its diverse clinical presentations and unique tumour biology.
Master switches of T-cell activation and differentiation
Authors: Beier K. C. , Kallinich T. , Hamelmann E.
Published: March 2007

T-cells play a central role in allergic airway diseases such as bronchial asthma. The imbalance between allergen-specific pro-inflammatory and pro-allergic T-cell responses on one hand and regulatory or suppressive T-cell responses on the other may best explain the development of unwanted immune responses against environmental allergens, which lead to immunoglobulin E production and airway inflammation. A key role in the fine tuning of any T-cell response is provided by the engagement of so-called co-stimulatory molecules that are required for the full activation of T-cells and the recognition of antigensviathe antigen-specific T-cell receptor. Many of these co-stimulatory molecules have been identified only recently, leading to a fundamental change in the overall understanding of T-cell regulation.

Due to their pivotal impact on T-cell differentiation and control, co-stimulatory molecules are promising targets for therapeutic intervention in T-cell-regulated or -mediated immune disorders, including allergic diseases and asthma. In the present article, an attempt is made to summarise the current knowledge on the basic concept of co-stimulation, the presently known co-stimulatory molecules and their various functions on T-cell activation or suppression. The mini-series will be completed by two more articles describing the recent experimental studies and preliminary clinical findings regarding the role of co-stimulatory molecules in allergic disorders and bronchial asthma, and a discussion regarding the feasibility of co-stimulatory molecules as potential targets for the treatment of allergic airway disease.

Although it is too early for any clinical implication or utilisation at this moment, the authors are convinced that a better understanding of co-stimulation in the context of allergic asthma will finally provide novel and promising approaches for treatment and prevention.
Depression and socio-economic risk factors: 7-year longitudinal population study
Authors: Lorant Vincent , Croux Christophe , Weich Scott , Deliège Denise , Mackenbach Johan , Ansseau Marc
Published: March 2007

Background

Low socio-economic status is associated with a higher prevalence of depression, but it is not yet known whether change in socio-economic status leads to a change in rates of depression.

Aims

To assess whether longitudinal change in socio-economic factors affects change of depression level.

Method

In a prospective cohort study using the annual Belgian Household Panel Survey (1992–1999), depression was assessed using the Global Depression Scale. Socio-economic factors were assessed with regard to material standard of living, education, employment status and social relationships.

Results

A lowering in material standard of living between annual waves was associated with increases in depressive symptoms and caseness of major depression. Life circumstances also influenced depression. Ceasing to cohabit with a partner increased depressive symptoms and caseness, and improvement in circumstances reduced them; the negative effects were stronger than the positive ones.

Conclusions

The study showed a clear relationship between worsening socio-economic circumstances and depression.
Population level of unmet need for mental healthcare in Europe
Authors: Alonso Jordi , Codony Miquel , Kovess Viviane , Angermeyer Matthias C. , Katz Steven J. , Haro Josep M. , De Girolamo Giovanni , De Graaf Ron , Demyttenaere Koen , Vilagut Gemma , Almansa Josué , Lépine Jean Pierre , Brugha Traolach S.
Published: March 2007

Background

The high prevalence of mental disorders has fuelled controversy about the need for mental health services.

Aims

To estimate unmet need for mental healthcare at the population level in Europe.

Method

As part of the European Study of Epidemiology of Mental Disorders (ESEMeD) project, a cross-sectional survey was conducted of representative samples of the adult general population of Belgium, France, Germany, Italy, The Netherlands and Spain (n=8796). Mental disorders were assessed with the Composite International Diagnostic Interview 3.0. Individuals with a 12-month mental disorder that was disabling or that had led to use of services in the previous 12 months were considered in need of care.

Results

About six per cent of the sample was defined as being in need of mental healthcare. Nearly half (48%) of these participants reported no formal healthcare use. In contrast, only 8% of the people with diabetes had reported no use of services for their physical condition. In total, 3.1% of the adult population had an unmet need for mental healthcare. About 13% of visits to formal health services were made by individuals without any mental morbidity.

Conclusions

There is a high unmet need for mental care in Europe, which may not be eliminated simply by reallocating existing healthcare resources.
Fair assessment of the merits of psychiatric research
Authors: Lewison Grant , Thornicroft Graham , Szmukler George , Tansella Michele
Published: March 2007

Background

Use of bibliometric assessments of research quality is growing worldwide. So far, a narrow range of metrics have been applied across the whole of biomedical research. Without specific sets of metrics, appropriate to each sub-field of research, biased assessments of research excellence are possible.

Aims

To discuss the measures used to evaluate the merits of psychiatric biomedical research, and to propose a new approach using a multidimensional selection of metrics appropriate to each particular field of medical research.

Method

Three steps: (a) a definition of scientific ‘domains', (b) translating these into ‘filters' to identify publications from bibliometric databases, leading to (c) the creation of standardised measures of merit.

Results

We propose using: (a) established metrics such as impact factor: and citation indices, (b) new derived measures such as the ‘worldscale’ score, and (c) new indicators based on journal peer esteem, impact on clinical practice, medical education and health policy.

Conclusions

No single index or metric can be used as a fair rating to compare nations, universities, research groups, or individual investigators across biomedical science. Rather, we propose using a multidimensional profile composed of a carefully selected array of such metrics.
Burden on caregivers of people with schizophrenia: Comparison between Germany and Britain
Authors: Roick Christiane , Heider Dirk , Bebbington Paul E. , Angermeyer Matthias C. , Azorin Jean-Michel , Brugha Traolach S. , Kilian Reinhold , Johnson Sonia , Toumi Mondher , Kornfeld Åsa
Published: March 2007

Background

Burden on the relatives of patients with schizophrenia may be influenced not only by patient and caregiver characteristics, but also by differences in mental health service provision.

Aims

To analyse whether family burden is affected by national differences in the provision of mental health services.

Method

Patients with schizophrenia and their key relatives were examined in Germany (n=333) and Britain (n = 170). Differences in family burden in both countries were analysed with regression models controlling for patient and caregiver characteristics.

Results

Family burden was associated with patients' symptoms, male gender, unemployment and marital status, as well as caregivers' coping abilities, patient contact and being a patient's parent. However, even when these attributes were controlled for, British caregivers reported more burden than German caregivers.

Conclusions

National differences in family burden may be related to different healthcare systems in Germany and Britain. Support for patients with schizophrenia may be shifted from the professional to the informal healthcare sector more in Britain than in Germany.
Therapeutic effect of follow-up assessments on antidepressant and placebo response rates in antidepressant efficacy trials
Authors: Posternak Michael A. , Zimmerman Mark
Published: March 2007

Background

It remains unclear how much various factors contribute to the placebo response.

Aims

To estimate the therapeutic impact of follow-up assessments on placebo response in antidepressant trials.

Method

Double-blind, placebo-controlled antidepressant trials that reported weekly changes in Hamilton Rating Scale for Depression (HRSD) scores over 6 weeks were selected. Included studies (n=41) were divided into those that conducted four, five or six follow-up assessments. Reductions in HRSD scores as a function of the different follow-up schedules were compared.

Results

An extra follow-up visit at week 3 was associated with a 0.86 further reduction in HRSD score; an extra visit at week 5 was associated with a 0.67 further reduction. These effects represented approximately 34–44% of the placebo response that occurred over these time frames. Two additional visits were associated with twice the reduction in HRSD score than one, suggesting that the therapeutic impact of assessment visits is cumulative and proportional. A comparable therapeutic effect was also found in participants receiving active medication.

Conclusions

Follow-up assessments in antidepressant treatment trials incur a significant therapeutic effect for participants on placebo, and this represents about 40% of the placebo response.
The Effect of Emergency Department Expansion on Emergency Department Overcrowding
Authors: Han Jin H. , Zhou Chuan , France Daniel J. , Zhong Sheng , Jones Ian , Storrow Alan B. , Aronsky Dominik
Published: March 2007

Objectives:
To examine the effects of emergency department (ED) expansion on ambulance diversion at an urban, academic Level 1 trauma center.

Methods:
This was a pre‐post study performed using administrative data from the ED and hospital electronic information systems. On April 19, 2005, the adult ED expanded from 28 to 53 licensed beds. Data from a five‐month pre‐expansion period (November 1, 2004, to March 1, 2005) and a five‐month postexpansion period (June 1, 2005, to October 31, 2005) were included for this analysis. ED and waiting room statistics as well as diversion status were obtained. Total ED length of stay (LOS) was defined as the time from patient registration to the time leaving the ED. Admission hold LOS was defined as the time from the inpatient bed request to the time leaving the ED for admitted patients. Mean differences (95% confidence interval [CI]) in total time spent on ambulance diversion per month, diversion episodes per month, and duration per diversion episode were calculated. An accelerated failure time model was performed to test if ED expansion was associated with a reduction in ambulance diversion while adjusting for potential confounders.

Results:
From pre‐expansion to postexpansion, daily patient volume increased but ED occupancy decreased. There was no significant change in the time spent on ambulance diversion per month (mean difference, 10.9 hours; 95% CI =−74.0 to 95.8), ambulance diversion episodes per month (two episodes per month; 95% CI =−4.2 to 8.2), and duration of ambulance diversion per episode (0.3 hours; 95% CI =−4.0 to 3.5). Mean (±SD) total LOS increased from 4.6 (±1.9) to 5.6 (±2.3) hours, and mean (±SD) admission hold LOS also increased from 3.0 (±0.2) to 4.1 (±0.2) hours. The proportion of patients who left without being seen was 3.5% and 2.7% (p = 0.06) in the pre‐expansion and postexpansion periods, respectively. In the accelerated failure time model, ED expansion did not affect the time to the next ambulance diversion episode.

Conclusions:
An increase in ED bed capacity did not affect ambulance diversion. Instead, total and admission hold LOS increased. As a result, ED expansion appears to be an insufficient solution to improve diversion without addressing other bottlenecks in the hospital.
Definition of Clinically Distinct Molecular Subtypes in Estrogen Receptor–Positive Breast Carcinomas Through Genomic Grade
Authors: Loi Sherene , Haibe-Kains Benjamin , Desmedt Christine , Lallemand Françoise , Tutt Andrew M. , Gillet Cheryl , Ellis Paul , Harris Adrian , Bergh Jonas , Foekens John A. , Klijn Jan G.M. , Larsimont Denis , Buyse Marc , Bontempi Gianluca , Delorenzi Mauro , Piccart Martine J. , Sotiriou Christos
Published: March 2007

Purpose

A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) –positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed.

Materials and Methods

We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high–or low–genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome.

Results

Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations.

Conclusion

The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.
Molecular Profiling Identifies Prognostic Subgroups of Pediatric Glioblastoma and Shows Increased YB-1 Expression in Tumors
Authors: Faury Damien , Nantel André , Dunn Sandra E. , Guiot Marie-Christine , Haque Takrima , Hauser Péter , Garami Miklós , Bognár László , Hanzély Zoltán , Liberski Pawel P. , Lopez-Aguilar Enrique , Valera Elvis T. , Tone Luis G. , Carret Anne-Sophie , Del Maestro Rolando F. , Gleave Martin , Montes Jose-Luis , Pietsch Torsten , Albrecht Stephen , Jabado Nada
Published: March 2007

Purpose

Pediatric glioblastoma (pGBM) is a rare, but devastating brain tumor. In contrast to GBM in adults (aGBM), little is known about the mechanisms underlying its development. Our aim is to gain insight into the molecular pathways of pGBM.

Materials and Methods

Thirty-two pGBM and seven aGBM samples were investigated using biochemical and transcriptional profiling. Ras and Akt pathway activation was assessed through the phosphorylation of downstream effectors, and gene expression profiles were generated using the University Health Network Human 19K cDNA arrays. Results were validated using real-time polymerase chain reaction and immunohistochemistry and compared with existing data sets on aGBM.

Results

There are at least two subsets of pGBM. One subset, associated with Ras and Akt pathway activation, has very poor prognosis and exhibits increased expression of genes related to proliferation and to a neural stem-cell phenotype, similar to findings in aggressive aGBM. This subset was still molecularly distinguishable from aGBM after unsupervised and supervised analysis of expression profiles. A second subset, with better prognosis, is not associated with activation of Akt and Ras pathways, may originate from astroglial progenitors, and does not express gene signatures and markers shown to be associated with long-term survival in aGBM. Both subsets of pGBM show overexpression of Y-box-protein-1 that may help drive oncogenesis in this tumor.

Conclusion

Our work, the first study of gene expression profiles in pGBM, provides valuable insight into active pathways and targets in a cancer with minimal survival, and suggests that these tumors cannot be understood exclusively through studies of aGBM.
Obesity in Survivors of Childhood Acute Lymphoblastic Leukemia and Lymphoma
Authors: Razzouk Bassem I. , Rose Susan R. , Hongeng Suradej , Wallace Dana , Smeltzer Matthew P. , Zacher Margie , Pui Ching-Hon , Hudson Melissa M.
Published: March 2007

Purpose

We evaluated the long-term effects of treatment on the body mass index (BMI) of children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma who received one of three CNS-directed therapies: intrathecal methotrexate with intravenous high-dose methotrexate (1 g/m2), intrathecal methotrexate with 18 Gy cranial radiation, or intrathecal methotrexate with 24 Gy cranial radiation.

Patients and Methods

Between 1979 and 1984, 456 children with newly diagnosed ALL and lymphoma were enrolled onto a single protocol at St Jude Children's Research Hospital (Memphis, TN). The heights and weights of 422 of the children were measured at diagnosis, during treatment, at the end of therapy, and approximately every 6 to 12 months thereafter. Patients who had attained their adult height at the time of analysis (n = 248) were placed in weight categories based on their BMI, BMI percentile, or weight-for-length percentile depending on age.

Results

The overall percentage of survivors who were overweight or obese approximated rates prevalent in the general population of the United States. Young age (< 6 years) and overweight/obesity at diagnosis were the best predictors of obesity at adult height. The rate of BMI increase did not differ significantly between children who received radiation and those who did not, nor between patients who received 18 or 24 Gy of cranial radiation.

Conclusion

BMI weight category at diagnosis, rather than type of CNS treatment received, predicted adult weight in long-term survivors of childhood hematologic malignancies.
Dehydroepiandrosterone Protects Vascular Endothelial Cells against Apoptosis through a Gαi Protein-Dependent Activation of Phosphatidylinositol 3-Kinase/Akt and Regulation of Antiapoptotic Bcl-2 Expression
Authors: Liu Dongmin , Si Hongwei , Reynolds Kathryn A. , Zhen Wei , Jia Zhenquan , Dillon Joseph S.
Published: March 2007

The adrenal steroid dehydroepiandrosterone (DHEA) may improve vascular function, but the mechanism is unclear. In the present study, we show that DHEA significantly increased cell viability, reduced caspase-3 activity, and protected both bovine and human vascular endothelial cells against serum deprivation-induced apoptosis. This effect was dose dependent and maximal at physiological concentrations (0.1–10 nm). DHEA stimulation of bovine aortic endothelial cells resulted in rapid and dose-dependent phosphorylation of Akt, which was blocked by LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), the upstream kinase of Akt. Accordingly, inhibition of PI3K or transfection of the cells with dominant-negative Akt ablated the antiapoptotic effect of DHEA. The induced Akt phosphorylation and subsequent cytoprotective effect of DHEA were dependent on activation of Gαi proteins, but were estrogen receptor independent, because these effects were blocked by pertussis toxin but not by the estrogen receptor inhibitor ICI182,780 or the aromatase inhibitor aminoglutethimide. Finally, DHEA enhanced antiapoptotic Bcl-2 protein expression, its promoter activity, and gene transcription attributable to the activation of the PI3K/Akt pathway. Neutralization of Bcl-2 by antibody transfection significantly decreased the antiapoptotic effect of DHEA. These findings provide the first evidence that DHEA acts as a survival factor for endothelial cells by triggering the Gαi-PI3K/Akt-Bcl-2 pathway to protect cells against apoptosis. This may represent an important mechanism underlying the vascular protective effect of DHEA.
Epidermal Growth Factor (EGF) Receptor Ligands in the Chicken Ovary: I. Evidence for Heparin-Binding EGF-Like Growth Factor (HB-EGF) as a Potential Oocyte-Derived Signal to Control Granulosa Cell Proliferation and HB-EGF and Kit Ligand Expression
Authors: Wang Yajun , Li Juan , Ying Wang Crystal , Yan Kwok Amy Ho , Leung Frederick C.
Published: March 2007

There is increasing evidence that epidermal growth factor (EGF) receptor (EGFR) ligand and Kit ligand (KL) play critical roles in controlling follicular development in mammals. Because little is known about their expressions in the ovary of nonmammalian vertebrate, our study aimed to examine the expression, hormonal regulation, and interaction of HB-EGF and KL in the chicken ovary. Using semiquantitative RT-PCR, we demonstrated that ovarian HB-EGF expression increased dramatically with the posthatching ovarian growth. In line with this finding, HB-EGF was shown to be produced primarily by the growing oocytes and capable of stimulating the proliferation of granulosa cells in prehierarchal (3 mm) and preovulatory follicles (F5 and F1). Although HB-EGF expression is mainly restricted to the oocytes, its expression in cultured granulosa cells could be transiently yet strongly induced by HB-EGF and other EGFR ligands including EGF and TGF-α. And the inducing effect of HB-EGF was completely abolished by AG1478 (10 μm) or PD98059 (100 μm), indicating that the action of HB-EGF is mediated by EGFR and intracellular MAPK/ERK signaling pathway. Unlike mammals, only KL-1, not the other three isoforms identified (KL-2, -3, and -4), was detected to be predominantly expressed in the chicken ovary. Interestingly, KL expression in undifferentiated and differentiated granulosa cells could be transiently down-regulated by HB-EGF, implying an intrafollicular communication between growing oocyte and surrounding granulosa cells through the interplay of EGFR ligand and KL. Collectively, our data suggest that HB-EGF is likely a paracrine signal from the oocyte to regulate granulosa cell proliferation and HB-EGF and KL expression during ovarian follicular development.
Receptor-Mediated Suppression of Cardiac Heat-Shock Protein 72 Expression by Testosterone in Male Rat Heart
Authors: Kohno Hiroaki , Takahashi Naohiko , Shinohara Tetsuji , Ooie Tatsuhiko , Yufu Kunio , Nakagawa Mikiko , Yonemochi Hidetoshi , Hara Masahide , Saikawa Tetsunori , Yoshimatsu Hironobu
Published: March 2007

The impact of testosterone on cardiac expression of heat-shock protein 72 (HSP72) remains to be elucidated. Male Sprague Dawley rats 10 wk of age (adult) were castrated. Four weeks later, testosterone (10 mg/kg, ip) was administered as a single dose, followed by the application of hyperthermia (HT) (43 C) at 6 h after testosterone administration. Twenty-four hours later, each heart was isolated. Cardiomyocytes were prepared from 3- to 5-d-old Wistar rats and male Sprague Dawley rats 10 wk of age. Testosterone (0.1–10 μm) was added to the medium, followed by the application of HT (42 C). Twenty-four hours later, cells were collected. We observed the following: 1) Exogenous testosterone suppressed HT-induced HSP72 expression, but castration alone had no influence. 2) HT resulted in better reperfusion-induced cardiac performance in castrated rats comparable with sham-operated rats, which was inhibited by testosterone. The number of apoptotic cells after ischemia/reperfusion was also increased by testosterone. 3) HT-induced HSP72 expression in cultured cardiomyocytes was suppressed by testosterone. 4) HT resulted in less damage to cells, including apoptosis, in response to hypoxia/reoxygenation, which was inhibited by testosterone. 5) Flutamide, a testosterone receptor blocker, cancelled the suppressive effects of testosterone on HSP72 expression. 6) The HT-induced increase in heat-shock factor 1 activity to bind to heat-shock element DNA was suppressed by testosterone, and this was reversed by flutamide. Our results indicate that testosterone potentially has inhibitory effects on cardiac HSP72 expression by modulating transcription, through testosterone receptor-mediated genomic mechanisms.
Suppression of Iodide Uptake and Thyroid Hormone Synthesis with Stimulation of the Type I Interferon System by Double-Stranded Ribonucleic Acid in Cultured Human Thyroid Follicles
Authors: Yamazaki Kazuko , Suzuki Koichi , Yamada Emiko , Yamada Tetsu , Takeshita Fumihiko , Matsumoto Misako , Mitsuhashi Tomoaki , Obara Takao , Takano Kazue , Sato Kanji
Published: March 2007

Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of human TSH, we studied the effects of polyinosinic-polycytidylic acid [Poly(I:C)], a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and retinoic-acid-inducible protein-1) comparable with the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-β, IFN-regulating factors, proinflammatory cytokines, and class I major histocompatibility complex (MHC), whereas genes associated with thyroid hormonogenesis (sodium/iodide symporter, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN α/β receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis.
Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear
Authors: Bok Jinwoong , Dolson Diane K. , Hill Patrick , Rüther Ulrich , Epstein Douglas J. , Wu Doris K.
Published: March 2007

Organization of the vertebrate inner ear is mainly dependent on localized signals from surrounding tissues. Previous studies demonstrated that sonic hedgehog (Shh) secreted from the floor plate and notochord is required for specification of ventral (auditory) and dorsal (vestibular) inner ear structures, yet it was not clear how this signaling activity is propagated. To elucidate the molecular mechanisms by which Shh regulates inner ear development, we examined embryos with various combinations of mutant alleles for Shh, Gli2 and Gli3. Our study shows that Gli3 repressor(R) is required for patterning dorsal inner ear structures, whereas Gli activator (A) proteins are essential for ventral inner ear structures. A proper balance of Gli3R and Gli2/3A is required along the length of the dorsoventral axis of the inner ear to mediate graded levels of Shh signaling,emanating from ventral midline tissues. Formation of the ventral-most otic region, the distal cochlear duct, requires robust Gli2/3A function. By contrast, the formation of the proximal cochlear duct and saccule, which requires less Shh signaling, is achieved by antagonizing Gli3R. The dorsal vestibular region requires the least amount of Shh signaling in order to generate the correct dose of Gli3R required for the development of this otic region. Taken together, our data suggest that reciprocal gradients of GliA and GliR mediate the responses to Shh signaling along the dorsoventral axis of the inner ear.
Generation of Human Monoclonal Allergen-Specific IgE and IgG Antibodies from Synthetic Antibody Libraries
Authors: Braren Ingke , Blank Simon , Seismann Henning , Deckers Susanne , Ollert Markus , Grunwald Thomas , Spillner Edzard
Published: March 2007

Background: Allergen-specific IgE and IgG antibodies play pivotal roles in the induction and progression of allergic hypersensitivity reactions. Consequently, monoclonal human IgE and IgG4 antibodies with defined specificity for allergens should be useful in allergy research and diagnostic tests. We used combinatorial antibody libraries and subsequent recombinant production to make and assess IgE, IgG1, and IgG4 allergen-specific antibodies.

Methods: We used phage display to select a synthetic single-chain antibody fragment (scFv) library against 3 different allergens, from bee venom, bovine milk, and apple. The scFv obtained were converted into IgG1, IgG4, and IgE antibody formats and assessed for their biochemical properties by ELISA, immunoblotting, and fluorescence-activated cell sorting.

Results: Two different antibody formats for each IgG1, IgG4, and IgE antibody were produced in mammalian cells as disulfide-linked and glycosylated Ig, which were usable in allergen-specific ELISA assays and immunoblots. In addition, the recombinant IgE antibodies mediated the binding of allergens to HEK-293 cells transfected with the high-affinity IgE receptor, and this binding was blocked by corresponding IgG antibodies.

Conclusions: The use of synthetic libraries for the generation of allergen-specific recombinant IgE and IgG antibodies should have broad applications in allergological research and diagnosis.
Behavioural Profiles and Injury Severity Following Childhood Traumatic Brain Injury
Authors: Barker-Collo Suzanne L.
Published: March 2007

Traumatic brain injury (TBI) is a leading cause of death and morbidity in children and can result in cognitive, behavioural, social and emotional difficulties that may impact quality of life. This study examined the impact of mild, moderate, and severe childhood TBI, when compared to severe orthopaedic injury, on behaviour as measured by the Child Behavior Checklist (CBCL) in a sample of 74 children with TBI and 13 with orthopaedic injury aged 4 to 13 years at the time of injury. Correlational analyses revealed that within the TBI sample increased anxiety/depression and somatisation were related to increased age at the time of injury and shorter inpatient hospital stay. Increased age was also related to increased parental reports of attention problems; while increased hospital stay was related to increased withdrawal and thought problems. Symptomatology was within normal limits for all groups, approaching the borderline clinical range in the moderate TBI group for somatic symptoms and in the severe TBI group for thought and attention problems. Those with severe TBI had more thought and attention problems, and to a lesser extent social problems, than those with mild or moderate TBI; while those with moderate TBI had the highest levels of somatic and anxious–depressed symptoms. The only scale where performance seemed to increase in relation to injury severity was the attention problems scale. It is suggested that the findings for those with moderate TBI reflect increased awareness of one's own vulnerability/mortality, with the implication that issues such as grief, loss, and mortality may need to be addressed therapeutically.
The Social, Emotional and Cultural Life of the Orbitofrontal Cortex
Authors: McDonald Skye
Published: March 2007

Formal assessment of the impact of frontal-lobe impairment on social and interpersonal function has been somewhat neglected relative to interest in documenting executive impairment on nonsocial tasks. Despite this, experimental evidence is accruing that attests to the role of the orbitomedial frontal lobes, the amygdala and related structures in the appraisal and interpretation of socially relevant stimuli. In this address the evidence regarding the frontal lobes and social cognition, that is, social information processing is reviewed. At least 3 different constructs have been proposed that appear to be mediated by cerebral systems encompassing the orbitomedial frontal cortex: (1) social schema or social knowledge networks that guide judgments and behavioural responses, (2) emotional processing, including both the ability to recognise different affective states in others and the ability to experience affective (somatic) responses to emotionally important environmental stimuli, and (3) theory of mind – the ability to conceptualise what others are thinking and feeling. On the basis of this recent experimental work it is argued that a variety of assessment techniques are becoming available that are both practical and potentially sensitive to psychosocial changes after frontal lobe damage.
Are Mexican American Adolescents at Greater Risk of Suicidal Behaviors?
Authors: Roberts Robert E. , Roberts Catherine Ramsay , Xing Yun
Published: March 2007

A reexamination of ethnicity as a risk factor for adolescent suicidal behavior, focusing on whether Mexican American youths are at increased risk, was undertaken. Data from a sample of 4,175 African, European, and Mexican Americans, aged 11–17, are presented. We examined lifetime attempts and past year attempts, thoughts, and plans. Odds ratios, adjusting for covariates, indicate no differences between European and Mexican Americans on past year thoughts, plans, or attempts or lifetime attempts. Although some studies have reported Mexican American youths are at increased risk, we did not find any differences. Possible explanations for disparate results across studies are discussed, in particular methods effects.
Economic Strain and Suicide Risk: A Qualitative Analysis
Authors: Stack Steven , Wasserman Ira
Published: March 2007

Research at the individual level on economic strain and suicide has focused on unemployment; yet it remains unclear how unemployment and other economic strains actually affect suicide risk for the individual. In the present study Agnew's (1992, 2002), General Strain Theory was applied to a qualitative analysis of case files. Strain issues assessed include the role of goal blockage, economic loss, noxious work environments, anticipated strain, strain clusters, and vicarious strain in the generation of suicide risk. Data are from 62 cases of suicide involving economic strain from the files of an urban county medical examiner's office. The cases were classified into strain categories. Suicide risk was related to all categories of strain; however, economic strains were typically comorbid with additional strains in the genesis of suicide. Key auxiliary strains included anticipated loss of a home place, loss of a car, noxious social relationships, medical problems, death of loved ones, and involvement with the criminal justice system. Some evidence was found linking economic strain to the suicides of nonimpoverished persons. Economic strain and suicide would especially benefit by testing additional hypotheses on strain comorbidity. Unemployment combined with an anticipated eviction from one's home is recommended as a particular point of departure for future work.
Racial Disparities in Mental Health Service Use by Adolescents Who Thought About or Attempted Suicide
Authors: Freedenthal Stacey
Published: March 2007

Differences in rates and predictors of mental health service use among 2,226 Black, Hispanic, and White adolescents (aged 12–17) who reported recent suicidal thoughts or an attempt were examined. Black adolescents were 65% (OR = .65, p < .05), and Hispanic adolescents were 55% (OR = .55, p < .001), as likely as White adolescents to report service use, even when controlling for need for care and ability to secure services. Suicide attempt and psychiatric symptoms each interacted with race to increase the odds of service use uniquely for White adolescents. Results indicate that racial disparities characterize adolescents' mental health service use even when suicide risk increases.
No‐Harm Contracts: A Review of What We Know
Authors: Lewis Lisa McConnell
Published: March 2007

Few events in the practice of a mental health clinician can be as devastating as the suicide of a client. Although suicide is a rare occurrence, clinicians face assessment of clients' risk for harming themselves on a regular basis. One well‐accepted and widely practiced intervention for suicidal ideation is the use of no‐harm contracts (NHC), although opinions about NHCs range from enthusiasm to apathy. The existing research does not support the use of such contracts as a method for preventing suicide, nor for protecting clinicians from malpractice litigation in the event of a client suicide.
Ethical, Legal, and Practical Issues in the Control and Regulation of Suicide Promotion and Assistance over the Internet
Authors: Mishara Brian L. , Weisstub David N.
Published: March 2007

The promotion of suicide and description of suicide methods on the Internet have led to widespread concern that legal control is mandated. Apart from value concerns pertaining to attitudes about suicide, the guarantee of freedom of expression presents a serious challenge to the introduction of restrictive laws. Recent developments in Australia and Europe are presented, noting jurisdictional complexity as an obstacle to effective application. Finally, scientific data of an epidemiological nature are revealed to be insufficient to warrant making causal assertions about the Internet and its relation to suicidal acts, including those of vulnerable populations. Recommendations are made with respect to public education, suicide prevention, and future research.
Analysis of a National Toll Free Suicide Crisis Line in South Africa
Authors: Meehan Sue‐Ann , Broom Yvonne
Published: March 2007

The first national toll free suicide crisis line for South Africa was launched in October 2003 with the aim of providing a service dedicated to the prevention of suicide in this country. The intervention was motivated by South Africa's suicide rate which had risen higher than the global suicide rate, with the majority of attempted suicides occurring among people younger than 35 years of age (WHO, 2002). Demographic characteristics of callers were identified to evaluate the perceived helpfulness of this crisis line, so as to inform planning and implementation of future suicide prevention programs. Results showed that the majority of callers were female; between the ages of 16 and 18 years; and lived in the provinces of Gauteng, North West, or KwaZulu Natal. Callers were more likely to be from urban than rural areas; were still at school, unemployed, or studying at a tertiary institution; and had not previously attempted suicide. The majority of participants did perceive the crisis line as helpful. The continued collection of demographic data from the crisis line is recommended so that South Africa can create an updated database of areas and sectors of the population that require suicide intervention, and for planning and implementing suicide prevention programs in this country.
Potential Modulated Attenuated Total Reflectance Spectroscopy of Prussian Blue Films on ITO
Authors: Araci Zeynep Ozkan , Runge Anne F. , Doherty Walter J. , Saavedra S. Scott
Published: March 2007

Potential modulated attenuated total reflectance (PM‐ATR) spectroscopy has been employed to study charge transfer processes in Prussian blue (PB) films deposited on indium tin oxide (ITO) electrodes. PM‐ATR is a planar waveguide‐based spectroelectrochemical technique in which the optical response of an electroactive film is measured as a function of applied potential and modulation frequency. The multiple internal reflection geometry of PM‐ATR provides a significant sensitivity advantage over the single external reflectance geometry that has been employed in most prior electroreflectance studies. The apparent electron transfer rate of PB on ITO obtained using PM‐ATR was compared to that obtained with conventional cyclic voltammetry; the respective rates, 0.33 ± 0.15 s−1 (n = 3) and 0.71 ± 0.37 s−1 (n = 10), are in good agreement.
Enhanced Infrared Absorption of C60 on Thin Evaporated Pd Island Films
Authors: Wadayama Toshimasa , Ohta Takaaki , Hatta Aritada
Published: March 2007

Infrared transmission spectra of C60 multilayers on thin Pd films deposited onto surface‐oxidized Si(100) and hydrogen‐terminated Si(111) substrates are reported. In both cases, the spectra in the 1500–1100 cm−1 region exhibited bands at 1444, 1429, and 1182 cm−1 due, respectively, to the Ag (2), T1u (4), and T1u (3) modes. The appearance of the Ag (2) mode, which is originally infrared inactive (Raman active), reveals electron transfer from the metal to chemisorbed C60. Indeed, increasing the thickness of C60, the Ag (2) mode intensity saturated more rapidly than the T1u (4) and T1u (3) modes. The originally infrared active T1u (4) and T1u (3) modes were enhanced in intensity depending upon the Pd thickness. Actually, while both substrates gave nearly the same magnitude of enhancement, the optimum Pd thickness was smaller on the hydrogen‐terminated surface than on the surface‐oxidized surface. On the other hand, the Ag (2) mode was less intense on the hydrogen‐terminated surface than on the oxidized surface, suggestive of a shortage of chemisorbed C60 and thus pointing out the importance of the metal film morphology. Indeed, Pd films deposited on the two substrates gave rise to quite different AFM images. We also show that, regardless of the substrate, the Ag (2) mode is an order of magnitude smaller than for Ag deposition, though no remarkable intensity differences were observed with respect to the T1u (4) and T1u (3) modes.
Normal Bands in Surface‐Enhanced Raman Scattering (SERS) and Their Relation to the Electron‐Hole Pair Excitation Background in SERS
Authors: Otto Andreas , Akemann Walter , Pucci Annemarie
Published: March 2007

Normal bands in SERS are bands of Raman‐active vibrations of adsorbates in the first layer, whose frequency is not shifted with respect to the condensed species. Here we show the experimental result, that the intensity of the N‐bands of C2H4 on cold‐deposited copper films in ultrahigh vacuum scales with the intensity of the broadband background of the SERS spectra at the frequency position of the N‐bands. This is demonstrated by changing the background by temperature annealing of the Cu film. Changing the laser wavelength proves that the background is Raman scattering by electron‐hole pair excitations. A simple model including electron scattering by surface roughness can explain the spectral shape of the background and the scaling of the N‐bands with the background. Probably we also can explain the appearance of the N‐bands in surface‐enhanced infrared absorption (SEIRA) within this model.
Functional aspects of genetic variability in the GH genomic region
Authors: Gloria-Bottini F , Amante A , Lucarelli P , Saccucci P , Martinoli R , Bottini E
Published: March 2007

Because of the small differences among genotypes, it would be difficult in basal conditions to detect the effect of genetic polymorphism in endocrine function, but this could emerge during provocative tests. We have studied four polymorphic sites of the GH gene region (17q24.2), MSPIA, MSPIB, BGLIIA, and BGLIIB. Gene and haplotype distributions in classes of growth retardation have been studied. The outcome of GH diagnostic test in relation to GH region genotypes has been evaluated by the analysis of area under the GH secretory curve. Ninety-eight growth retarded children have been studied. On the basis of provocative GH test these children were classified as total GH deficit (TD), partial GH deficit (PD), and familial short stature (FSS) with no deficit of GH. Sixty-three healthy controls were also considered. An increased frequency of MSPIA*2 allele in PD and TD as compared with FSS children and controls has been observed suggesting that this allele is associated with a decreased GH release. BGLIIA*2 allele appears decreased in PD and TD as compared with FSS and controls, suggesting that this allele is associated with an increased release of GH. Carriers of MSPIA*2 allele show a lower GH release as compared with MSPIA *1/*1 subjects on the provocative test by insulin, while carriers of BGLIIA*2 allele show a higher GH release as compared with BGLIIA *1/*1 subjects on the provocative test by clonidine. The functional aspects of genetic variability within the GH genomic area parallel the genetic differences observed between TD and PD versus FSS and control children.
Regulation of Leydig cell steroidogenesis by extracellular signal-regulated kinase 1/2: role of protein kinase A and protein kinase C signaling
Authors: Manna Pulak R , Jo Youngah , Stocco Douglas M
Published: March 2007

The steroidogenic acute regulatory (StAR) protein plays a central role in the regulation of steroid biosynthesis. While steroidogenesis is influenced by many processes, their modes of actions, in a few cases, remain obscure. In this study, we explored the mechanism of action of one such signaling pathway, the extracellular signal-regulated kinase 1/2 (ERK1/2), in regulating StAR expression and steroidogenesis in conjunction with the protein kinase A (PKA) and protein kinase C (PKC) pathways. Using MA-10 mouse Leydig tumor cells, we demonstrate that the activation of PKC and PKA signaling, by phorbol-12-myristate-13-acetate (PMA) and dibutyryl cAMP (dbcAMP)/human chorionic gonadotropin (hCG) respectively, was able to phosphorylate ERK1/2, an event markedly decreased by an upstream kinase inhibitor, U0126. Treatment with PMA enhanced StAR protein expression (associated with a slight increase in progesterone synthesis) but not its phosphorylation (P-StAR), which, in contrast, coordinately increased in response to dbcAMP/hCG. Inhibition of ERK1/2 activity by U0126 decreased PMA-treated StAR expression but increased dbcAMP/hCG-mediated StAR and P-StAR; however, progesterone levels were attenuated. U0126 was found to affect StAR expression and steroidogenesis both at the transcriptional and translational levels. Further studies demonstrated that the effect of U0126 on PMA- and dbcAMP/hCG-mediated StAR expression and steroid synthesis was tightly correlated with the expression of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) and scavenger receptor class B type 1 (SR-B1). In fact, both DAX-1 and SR-B1 appear to play important roles in hormone-regulated steroidogenesis. These findings clearly demonstrate that the ERK1/2 signaling cascade involved in regulating StAR expression and steroid synthesis is mediated by multiple factors and pathways and is stimulus specific in mouse Leydig cells.