Step-Up Therapy Improves Asthma Control in Children

From Medscape Medical News
Deborah Brauser

March 3, 2010 (New Orleans, Louisiana) — Children with asthma who continue to have symptoms while using low-dose inhaled corticosteroids (ICS) can benefit from “stepping up” treatment by increasing the dosage or adding either a long-acting beta agonist (LABA) or a leukotriene-receptor antagonist (LTRA), according to a new triple-crossover randomized study called BADGER (Best Add-On Therapy Giving Effective Responses).

In fact, 98% of the study participants showed a significant improvement in asthma control after the addition of at least 1 of these options, according to research presented here at the American Academy of Allergy, Asthma and Immunology (AAAAI) 2010Annual Meeting and published online simultaneously in The New England Journal of Medicine.

Although the overall best response was achieved by adding a LABA, many of the children had a best response with one of the other step-up treatments, “highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy,”

He added that factors such as baseline Asthma Control Test (ACT) score, the absence of eczema, and race might also help clinicians to “better predict which of the 3 treatment options will help a patient the most.”

Past Step-Up Evidence Lacking

Although clinicians usually agree on treatments going from step 1 (intermittent asthma) to step 2 (persistent), the few studies that have been conducted on how to best treat children whose asthma is poorly controlled while receiving low-dose ICS have shown inconsistent results, reported Dr. Lemanske.

“The evidence to guide step-up therapy is lacking,” he told Medscape Allergy and Clinical Immunology. “So we wanted to answer the question: What is the best way to go from step 2 to step 3?”

Researchers from 5 centers (in 4 states), making up the National Heart, Lung, and Blood Institute–funded Childhood Asthma Research and Education Network, worked on the BADGER trial.

They sought to conduct a comparison study to establish not only which step-up therapy was best, but also “whether there are phenotypic or genotypic characteristics that can be used to predict whether a child will have a better response to one particular treatment than to another.”

A total of 498 children between the ages of 6 and 17 years with mild to moderate asthma were enrolled between March 2007 and July 2008, with 157 (65.4% male; mean age, 10.8 years) receiving each of the 3 step-up treatments in random order for 16 weeks each.

These treatments were the standard low-dose ICS (100 µg of fluticasone twice daily) plus either the LABA salmeterol (50 µg twice daily) or the LTRA montelukast (5 or 10 mg daily), or 2.5 times the standard ICS dose (250 µg fluticasone twice daily) only. Each patient also received a metered-dose inhaler of albuterol and prednisone.

At the end of each 16-week period, the number of days that the asthma symptoms were under control, lung function, and the number of exacerbations and attacks were measured before the patient moved on to the next treatment option.

Methods used included the Pediatric Asthma Quality of Life Questionnaire, the ACT (with scores from 0 to 27), spirometry tests, and patient- or guardian-recorded diary entries.

A Place for All 3 Therapies

The results, concentrating on the 165 patients who completed at least 2 study periods, showed that “although our goal was for 25% of the patients to see a difference in their asthma symptoms after using at least 1 of the treatments, we were surprised to see that 161 showed substantial improvement [P

The best response was shown in almost 40% of the patients by adding the LABA, in 30% by adding the LTRA, and in 28% by increasing the dose of ICS.

Using rank-ordered logistic regression, the predicted response to the LABA addition was significantly better than to the addition of the LTRA (relative probability [RP], 1.6; 95% confidence interval [CI], 1.1 – 2.3; P = 0.004) and the ICS step-up (RP, 1.7; 95% CI, 1.2 – 2.4; P = .002).

“In other words, the LABA was more than one and a half times as likely to produce the best response,” explained Dr. Lemanske.

“All 3 therapies clearly have a place in the management of kids with persistent asthma not well controlled on low-dose [ICS] alone,” said investigational team member Leonard B. Bacharier, MD, from the Department of Pediatrics at Washington University in St. Louis, Missouri, in a press release. “Statistically, LABA therapy was most likely to help the most patients, but it’s hard to look at an individual patient and know which one to choose.”

Significant predictor factors included ACT score, eczema, and race.
LABA treatment was the best add-on therapy for patients with an ACT score greater than 19 (P = .009). However, “if it was 19 or under, there was no difference among the therapies in producing a differential response,” reported Dr. Bacharier.

Although patients who had eczema did well on any of the 3 treatments, those who did not have eczema did better on the LABA.

The LABA was also most likely to give the best response in whites. The LABA and higher-dose ICS were equally likely to show the best response in African Americans, whereas the LTRA was least likely.

Factors that were not found to be significantly predictive of a drug’s effectiveness included age, sex, allergies, bronchodilator response or reversibility, and number of recent exacerbations.

Dr. Lemanske said that although he was disappointed to not find more predictors, “we’re not done analyzing and still have lots of genotyping to do.”

A Ceiling Effect for Low-Dose ICS

“Overall, our findings suggest that there is a ceiling effect of low-dose [ICS] in many, though not all, children, and that the addition of a different class of medication is often required to achieve improvements in asthma control,” said Dr. Lemanske. “The important take-home message is that if you choose something at step 3 and you’re not happy with it, based on the control, instead of pushing it up to step 4, look to one of these other treatments.”

He noted, however, that none of the study treatments provided perfect asthma control, and that there were still 120 asthma exacerbations or attacks among the patients who required rescue medication with prednisone. “We obviously still need to do more work.”

When asked about the recent mandates of the US Food and Drug Administration (FDA) on the need to lower the use of LABAs in patients with controlled asthma, Dr. Lemanske said that that was like comparing apples and oranges.

“The FDA was talking about step-down treatment, and our study was on step-up therapy for patients who did not have control of their asthma. Also, BADGER was an efficacy trial and we were not powered to look at safety outcomes. The duration of our trial and the size of our sample precluded statements regarding long-term risks.”

In the journal article, the authors write that “clinicians who prescribe LABAs (never to be used as monotherapy) in combination with [ICS] should continue to evaluate risk-benefit ratios.”

N Engl J Med. Published online March 2, 2010.

Stress control with pranyama

Our busy and tedious lifestyles produce lots of stress. Stress has a tremendous influence on our behaviour and attitude towards life. People get indulged in smoking, intake of alcohols, overeating etc.
Stress induces adverse effects on our normal body system such as circulatory and digestive system. The symptoms of the physiological disorders include nausea, diarrhea, acne, eczema, cold feet, palpitations etc.
Pranyama is the solution to all such problems. It is an efficacious stress buster tool that encompasses varied postures, asanas and poses. Pranayama should be practiced on a regular basis. It is a gamut of breathing exercises that maintains a harmony between the mind and body. It offers you mental composure. However, it should be clear in mind that pranayama should be done under the strict supervision of a strict professional. It relieves you of the stress and anxiety and helps you to acquire spiritual growth.

Yaz: A Extremely Controversial Start Control Pill

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Adversarial Reactions to Yaz

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Asthma : Severity and Control

IS IT ASTHMA?

LEVELS OF ASTHMA CONTROL

ASTHMA SEVERITY

ASTHMA EXARCEBATION

A115262

Illness perception in pediatric somatization and asthma: complaints and health locus of control beliefs.(Research) - Child and Adolescent Psychiatry and Mental Health

Authors: Lutz Goldbeck (corresponding author) [1]; Silke Bundschuh [2]

Background

Somatoform disorders and asthma bronchiale are two of the most frequent chronic conditions in childhood and adolescence with prevalence rates between 2.7 per cent [1] and 13.1 per cent for somatization including pain disorder [2] and between 4.25 per cent [3] and 9.3 per cent [4] for asthma. In both conditions cognitive-behavioral interventions aim to change patients’ and their caregivers’ maladaptive perceptions and enhance adaptive cognitive strategies [5]. The effectiveness of cognitive-behavioral treatments has been demonstrated for somatoform disorder such as recurrent abdominal pain in children [6] and for the improvement of adherence to treatment regimens in children and adolescents with asthma [7]. Thus, the usefulness of addressing the patients’ cognitions seems to be evident. However, only few studies have investigated illness concepts in pediatric patients and their caregivers. Therefore our knowledge of the patients’ illness-related cognitions is limited.

The patients’ perception and evaluation of somatic symptoms are considered important for subsequent illness behavior and coping with the disease. Somatoform disorders are characterized by a specific way of exaggerated attention to and negative evaluation of bodily sensations [8, 9]. Whereas patients who somatize are considered over-sensitive regarding their bodily functions [10], patients with asthma bronchiale need to monitor their pulmonary function and perceive early symptoms of dyspnea to utilize medical treatments before the onset of severe states of asthma [11].

The locus of control construct refers to the subjective beliefs of control that patients have over illness and health. Applying Rotter’s social learning theory [12] to patients with chronic diseases, three different styles of health- and illness-related locus of control cognitions have been described, representing illness experiences and generalized expectancies of symptom control [13].

Internal locus of control represents the belief that one’s own behavior is regarded as important for one’s state of health. This attitude is regarded as an essential pre-condition for active coping strategies both in patients with somatoform disorder and asthma. Social externality means that powerful others, for example parents or physicians, are considered as important for symptom control. This concept triggers the help-seeking behavior of patients. Patients with fatalistic health locus of control beliefs are convinced that their health state is influenced by fate, luck or random events. Fatalistic expectations are considered maladaptive in both somatoform disorder and asthma because of the associated passive patient behaviour [14].

In pediatric patients, the responsibility of parents for the illness behavior of their children and the caregivers’ impact on the development of the children’s own subjective health concepts have to be considered. Parents monitor their children’s health state, decide whether medical care is to be sought and comply with medical recommendations or not. The children’s and adolescent’s illness-related perceptions may be influenced by parental models and suggestions [15, 16]. On the other hand, different stages of cognitive development are known to determine subjective illness concepts [17, 18], thus systematic differences between children and adults are proposed. So far there are few studies on the relationship between parents’ and children’s illness concepts. Perrin and Shapiro [13] reported absent correlations between parental and children’s health locus of control perceptions. Such different viewpoints of parents and their children might complicate intervention planning.

To our knowledge, so far no studies have compared the health locus of control beliefs of children and adolescents with somatoform disorder and with asthma bronchiale, and the corresponding parental perceptions and cognitions. The comparison of subjective illness representations would contribute to answer the question whether disease-specific cognitions have to be addressed in cognitive behavioral interventions. Moreover, the comparison of patients’ and their caregivers’ perceptions would allow differential planning of family-oriented psychoeducational interventions. In this exploratory study, two research questions are addressed:

1) Do patients and their parents develop disease-specific health- and illness-related locus of control beliefs? As medical treatment in combination with the patients’ active role in symptom control is effective for asthma but not for somatoform disorder, we would expect more social external and internal health locus of control beliefs in the asthma patients and their caregivers, compared with patients with somatoform disorder and their caregivers.

2) Are parental proxy-reports and patients’ self-reports on somatic complaints and locus of control beliefs correlated? In accordance with previous findings in pediatric recurrent abdominal pain [19] and several other chronic conditions [13], we hypothesized a weak or absent association between children’s and parental symptom reports and illness concepts.

Method

Design and procedures

Informed consent of caregivers and assent of children and adolescents to participate in the study were obtained in accordance with the principles of the local ethical committee. The assessment was done by a researcher independently from the physicians and therapists responsible for the patients’ treatment. All participants filled in standardized questionnaires, the caregivers provided additional information about individual illness history, and socio-demographic data. Patients and caregivers filled in the questionnaires independently from one another.

Sample

Patients between 8 and 18 years of age with a clinical diagnosis of somatoform disorder or asthma bronchiale and their primary caregivers were included (for details see table 1). The study sample represented a consecutive number of patients who were eligible for the study at the participating study centres within a certain time frame. Mothers were the most frequent parental responders (86%) in both clinical groups. Younger children and mentally retarded patients were excluded, because they were not able to read and answer the questionnaires. Twenty-five children and adolescents with different subtypes of somatoform disorders and their primary caregivers were approached at specialized psychosomatic outpatient units of two university clinics. The spectrum of diagnoses included broadband somatization symptoms, autonomous dysfunction, and pain disorders. Diagnoses had been established by clinical psychologists or psychiatrists according to ICD-10 F45.x diagnostic criteria (equals DSM IV 300.81 somatization disorder or undifferentiated somatoform disorder; 307.80 chronic pain disorder associated with psychological factors; or 307.89 chronic pain disorder associated with both psychological and a general medical condition). Twenty-five inpatients with asthma bronchiale (ICD-10 J45.x) and their caregivers were recruited within the first few days after admission to a rehabilitation centre for pediatric pulmonology. The study participants with asthma represented rather a selection of non-responders to treatment within the system of primary healthcare. No significant between-group differences appeared at a level of

p Table 1 caption: Medical and socio-demographic characteristics of study sample [table omitted]

Measures

Subjective complaints were assessed with the

Giessen Complaint List for Children and Adolescents (GBB-KJ [20]). This multi-dimensional self-report questionnaire contains a broad range of different subjective somatic complaints. The child or adolescent is asked to report the frequency of each complaint on a 5-point rating scale (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = permanent). A parallel parent-form measures proxy-perceptions of their child’s symptoms. Five subscales with seven items each measure the dimensions fatigue, gastrointestinal symptoms, limb pain, circulation symptoms , and symptoms of a cold . A total score indicating severity/diversity of complaints is calculated by summing the raw scores of the five subscales. Good reliability and validity has been reported previously [21]. In the present study, internal consistency scores were between [alpha] = .74 and [alpha] = .85 for the subscales and .89 respectively .90 for the global complaint scale.

The

Multidimensional Health Locus of Control Scale (German version: KKG [22]) measures three dimensions of perceived controllability of individual health and illness symptoms: internal health locus of control, social external locus of control, and fatalistic external locus of control. Each scale consists of seven items with different perceptions of controllability of health- and illness-related aspects. On 6-point rating scales (1 = do not agree to 6 = agree very strongly) the degree of assent to each statement has to be indicated by the respondent. The questionnaire has been developed and validated with different clinical and healthy groups of children, adolescents and adults. It has good reliability and validity. In our study, the internal consistency was [alpha] = .68 for the socio-external scale, .85 for the fatalistic-external scale, and .87 for the internal dimension.

In order to receive additional parental reports, we modified the

KKG for the perspective of caregivers by rewording the items, for example ‘If my son/daughter has complaints, we ask somebody for advice’ instead of ‘If I have complaints, I ask somebody for advice.’ Cronbach’s [alpha] for the parent form was .66 for the socio-external scale, .72 for the fatalistic external scale and .79 for the internal locus of control dimension.

Statistical analyses

A descriptive analysis of the different scores was performed separately for both clinical groups and both informants. There were no statistically significant differences in socio-demographic and clinical characteristics between the two diagnostic groups. A series of 2 x 2 ANOVARs was computed with diagnosis (somatoform disorder, asthma) as between-subject factor and different dimensions of self-reported and caregiver-reported locus of control beliefs as repeated measures within-subject variables.

Pearson correlations between self-reports and parental proxy-reports in corresponding scales of the questionnaires were calculated to determine inter-rater concordance. We also calculated intra-class correlations, and the resulting scores were approximately the same as indicated by the Pearson correlations. To avoid redundant information, only Pearson coefficients are reported. A significance level of [alpha] = .05 was chosen. With regard to the explorative character of the study and to reduce the risk of [beta] -errors, no adjustment of significance level for multiple testing was made.

Results

Complaints

A broad variance of different complaints was found within both clinical groups, as reported by patients and caregivers in the

Giessen Complaint List for Children and Adolescents (GBB-KJ [20]). On the level of syndrome scales, self-reported fatigue and gastrointestinal symptoms in the psychosomatic patients and parent-reported cold symptoms in the asthma group were most frequent. On the single-symptom level, self-reported and parent-reported cough was the most frequent symptom in the asthma group, self-reported and parent-reported headache and abdominal pain were the most frequent single symptoms in the somatization group. Psychosomatic patients and their parents reported significantly more symptoms compared with pulmonologic patients, especially in the gastrointestinal and circulation dimensions.

Health locus of control

The most prominent manifestation of health locus of control perceptions was the parental

fatalistic locus of control perception in the asthma group (mean = 33.1, SD = 6.0), whereas the least manifestation of health locus of control was found in the asthma patients internal dimension (mean = 21.1, SD = 6.5). No significant differences in health locus of control estimations were demonstrated between the diagnostic groups (see table 2). However, there were significant main effects of perspective. In the internal and fatalistic locus of control perceptions parents scored higher than patients. In the fatalistic control perception there was a statistical trend towards a greater advantage of the parents vs. their children in the asthma group compared with the somatization group. Across both clinical groups, the multidimensional profiles of health locus of control beliefs revealed a significant preference of fatalistic external health control beliefs in the parents (mean = 30.6, SD = 6.5), compared to less frequent internal (mean = 27.7, SD = 5.4) and even lesser socio-external health control beliefs (mean = 24.7, SD = 5.0; ANOVA : F = 18.9, p F = 1.3, ns).Table 2 caption: Effects of diagnosis1 and perspective2 on health locus of control beliefs3 [table omitted]

Associations between parental and self-report data

Correlational analyses demonstrated weak associations between patients’ and parents’ reports, both separately within the clinical groups and in the total study sample (see table 3). Symptom reports were correlated significantly on a low to moderate level. Parent-patient correlations appeared slightly stronger in the psychosomatic group, compared with the asthma group, especially in the circulation and gastro-intestinal symptom scores. The only significant inter-rater correlation in the health locus of control perceptions could be demonstrated for the internal dimension, due to a moderate parent-patient concordance in the psychosomatic group. Interaction effects of diagnosis and informant occurred in the complaint list

total score and in the cold subscale, demonstrating a parental under-estimation of children’s subjective symptoms in the somatization group and a parental over-estimation of symptoms in the asthma group.Table 3 caption: Patient-caregiver concordance (Pearson correlations) in corresponding complaint scores1 and health locus of control dimensions2 [table omitted]

Discussion

This study investigates differential effects of diagnosis (somatoform disorder vs. asthma) on subjective illness-related cognitions and compares patients’ and their caregivers’ health- and illness-related symptom perceptions and locus of control evaluations.

The analysis of the locus of control beliefs demonstrate differences between parental and patients’ cognitions, but not between patients or parents of different diagnostic groups. Across both diagnostic groups parents have more pronounced control beliefs than their children. This finding is significant for the internal and fatalistic health locus of control dimension, whereas only a statistical trend occurs in the difference between caregivers and patients in the socio-external control attribution.

The attribution of symptoms to fate or chance indicates a sense of lack of control on illness, and consequently high scores of fatalistic-external locus of control are rather expected correlated with passive illness behavior and non-adherence to treatment. According to our results, especially parents of children and adolescents with asthma develop high fatalistic beliefs, indicating a lack of subjective predictability of their children’s asthma symptoms so far. This might be due to the long history of ineffective asthma treatment in our study sample. However, the asthma patients themselves report no significantly elevated fatalistic-external control perceptions compared with their internal or socio-external attributions of symptom control. In another study with the same instrument Schmitt et al. [14] found even a lower level of fatalistic locus of control beliefs in adolescent patients with asthma. A selection bias may be responsible for this finding, because in our study sample the patients were younger and non-response to standard treatment was a frequent reason for admission to inpatient rehabilitation.

Another relevant finding is that the asthma patients in our study sample reported low scores of perceived internal controllability of symptoms. Internal health locus of control has been demonstrated as associated with adherence to treatment [23] and should therefore be enhanced by therapists. Both results – the low internal control attribution of asthma patients and the high fatalistic control perception of their caregivers indicate the need for patient education and training.

The differences between the patients’ and their caregivers’ health related locus of control beliefs might also be explained by developmental differences of cognitive functioning. The belief that health cannot be controlled and that fate or chance might be responsible for staying healthy or becoming ill, requires the awareness of limited personal power. Due to their tendency towards concrete and rather egocentric thinking, children may overestimate their personal impact or the influence of powerful others on their health.

Our results demonstrate the ubiquity of subjective illness concepts across both chronic conditions. These findings are consistent with those of Perrin and Shapiro [13] who found no disease-specific control attributions of mothers with chronically ill children. Absence of disease specific locus of control beliefs may be explained with similar experiences of both clinical groups. Somatoform disorders and asthma bronchiale are both chronic conditions without prognosis of immediate cure, and both clinical subgroups had a longer history of ineffective treatment within the primary healthcare system before entering our study.

With regard to our second research question, we demonstrated that accordance between parents and patients is limited both in terms of symptom reports and cognitive illness concepts. Symptom reports were correlated only moderately. Consistent with the different diagnoses, children and adolescents with somatization disorder reported significantly more symptoms than peers suffering from asthma bronchiale. However, this judgment is not supported by the parents, who reported a similar level of symptoms in both clinical groups. Several explanations for this discrepancy between self reports and parent reports are possible. First, the ability of caregivers to recognize and report internal perceptions of their children reliably may be limited [19]. Patients may conceal some of their symptoms from their parents, and therefore parents cannot give valid reports on their child’s subjective health status. Secondly, the discrepancies may be due to reporter biases. Patients who somatize may aggravate their symptoms because they need to legitimate their illness state, and their parents may be non-respondents to attention-seeking strategies of their children, which become manifest in somatic complaints [16]. Asthma patients may have successfully adapted to their disease and consequently developed a recall bias, neglecting and under-reporting the negative aspects of their disease. On the other hand, parents of asthma patients may over-estimate the severity of their children’s symptoms because of a fearful monitoring, thus becoming over-sensitive for indicators of restricted physical well-being in their ill child [24]. As demonstrated previously in the study of Perrin and Shapiro [13], self-reported and parent proxy-reported health locus of control attributions were only moderately correlated in the internal dimension and not at all correlated in the external dimensions.

In summary, the results of our study demonstrate substantial differences between patients’ and parental illness-related perceptions, whereas subjective illness concepts varied independently of diagnosis.

Several limitations of this study should be mentioned. First, the results have to be considered as preliminary because of its possible selection bias. The participants with psychosomatic disorder may have been altered in their health- and illness-related cognitions by impact of psychological or psychiatric diagnosis and/or treatment compared with non-referred psychosomatic patients. The participants with asthma were referred to a specialized inpatient rehabilitation program, therefore they may have been more resistant against basic patient education and counselling than average pediatric asthma patients in outpatient settings. It can be assumed that our asthma sample represents rather non-responders to treatment within primary care, so these patients might be more difficult to treat and even more altered in their health perceptions and illness beliefs. With regard to these limitations due to selection, our results cannot be generalized to all patients with somatoform disorder or asthma.

Secondly, the small sample size may have concealed small between-group differences because of a limited statistical power. Large scale studies comparing different diagnostic subgroups might be able to detect differences that did not occur in our study because of its restricted sample size.

Moreover, the findings in this study are based on standard self-report measures. The socio-external health locus of control scale suffered from sub-optimal internal consistency of [alpha]

However, our preliminary results contribute some interesting findings to the emerging literature on symptom perception and cognitive aspects of chronic pediatric conditions. For the first time, we evaluated the health locus of control perceptions of children with Somatizationand their parents, and found similar cognitions as found in pediatric asthma. Future studies should include larger samples in different clinical settings and multi-method designs. Longitudinal studies would be necessary to get information on changes of subjective illness perceptions and cognitions.

Conclusion

Some clinical implications emerge from our findings. Our results indicate the relevance of multi-informant strategies in the diagnosis of health- and illness-related perceptions and cognitions in pediatric patients. Collecting parallel self-reports and caregiver reports of symptoms and health locus of control attributions should be an obligatory part of diagnosis. Such a comprehensive diagnosis is useful for planning patient education and counselling. Our findings highlight the importance of exploring patients and their caregivers separately to get valid information on subjective symptoms and illness concepts. Patients themselves may be regarded as more reliable informants about somatic symptoms, whereas both the patients’ and their caregivers’ subjective illness concepts are relevant for targeting cognitive-behavioral interventions. The degree of patient-parent accordance is an additional relevant aspect of diagnosis and intervention planning. Clinicians have to consider different subjective viewpoints of chronically ill children and their caregivers, and cognitive-behavioral interventions have to take into account these different health and illness concepts.

Competing interests

The author(s) declare that they have no competing interests.

Authors’ contributions

LG conceived in the study, participated in its design and coordination, performed the statistical analyses and drafted the manuscript. SB participated in the design, collected the data, and helped to analyse the data. Both authors read and approved the final version of the manuscript.

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Author Affiliation:

[1] Department of Child and Adolescent Psychiatry/Psychotherapy, University Hospital Ulm, Steinhoevelstr. 5, D-89075 Ulm, Germany

[2] Department of Pediatrics, University Hospital Ulm, Prittwitzstr. 43, D-89075 Ulm, Germany

Author Email: Lutz Goldbeck – lutz.goldbeck@uniklinik-ulm.de; Silke Bundschuh – silke.bundschuh@uniklinik-ulm.de

Article history:

Received Date: 2/26/2007

Accepted Date: 7/16/2007

Published Date: 7/16/2007

Article notes:

� 2007 Goldbeck and Bundschuh; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.