Analysis of complex physiological systems by information flow: a time scale-specific complexity assessment.

In the last two decades conventional linear methods for biosignal analysis have been substantially extended by non-stationary, non-linear, and complexity approaches. So far, complexity is usually assessed with regard to one single time scale, disregarding complex physiology organised on different time scales. This shortcoming was overcome and medically evaluated by information flow functions developed in our research group in collaboration with several theoretical, experimental, and clinical partners. In the present work, the information flow is introduced and typical information flow characteristics are demonstrated. The prognostic value of autonomic information flow (AIF), which reflects communication in the cardiovascular system, was shown in patients with multiple organ dysfunction syndrome and in patients with heart failure. Gait information flow (GIF), which reflects communication in the motor control system during walking, was introduced to discriminate between controls and elderly patients suffering from low back pain. The applications presented for the theoretically based approach of information flow confirm its value for the identification of complex physiological systems. The medical relevance has to be confirmed by comprehensive clinical studies. These information flow measures substantially extend the established linear and complexity measures in biosignal analysis.     

Spatial and temporal organization of TrkB expression in the developing musculature of the mouse esophagus

TrkB expression was investigated immunocytochemically in the developing musculature of mouse esophagus using conventional and confocal laser scanning microscopy. To demonstrate spatial relationships of TrkB immunoreactive cells to striated and smooth muscle fibers we combined TrkB immunocytochemistry with fluorochrome-tagged alpha-bungarotoxin for labeling of nicotinic acetylcholine receptors, and alpha-smooth muscle actin for labeling of smooth muscle cells. At developmental stages E15 to P7, TrkB immunoreactive cells transiently occurred in a transformation zone where striated intermingled with smooth muscle fibers. This transformation zone started in the rostral esophagus at E15, moved caudally, and disappeared between P7 and P10 in the caudal esophagus. The first TrkB-immunoreactive cells appeared in the outer muscle layer at E15. No TrkB-positive cells exhibited acetylcholine receptor clusters or were positive for alpha-smooth muscle actin. A few showed slight alpha-bungarotoxin staining over their entire surface. Taken together, the appearance of TrkB-expressing cells in the transformation zone suggest a role in muscle transdifferentiation. Alternatively, these results, together with recent in vitro data, suggest that TrkB is expressed in a subpopulation of myoblasts in which acetylcholine receptor clustering may be inhibited through a TrkB-mediated pathway.     

Complexity of multitrophic interactions in a grassland ecosystem depends on plant species diversity

1.?We studied the theoretical prediction that a loss of plant species richness has a strong impact on community interactions among all trophic levels and tested whether decreased plant species diversity results in a less complex structure and reduced interactions in ecological networks. 2.?Using plant species-specific biomass and arthropod abundance data from experimental grassland plots (Jena Experiment), we constructed multitrophic functional group interaction webs to compare communities based on 4 and 16 plant species. 427 insect and spider species were classified into 13 functional groups. These functional groups represent the nodes of ecological networks. Direct and indirect interactions among them were assessed using partial Mantel tests. Interaction web complexity was quantified using three measures of network structure: connectance, interaction diversity and interaction strength. 3.?Compared with high plant diversity plots, interaction webs based on low plant diversity plots showed reduced complexity in terms of total connectance, interaction diversity and mean interaction strength. Plant diversity effects obviously cascade up the food web and modify interactions across all trophic levels. The strongest effects occurred in interactions between adjacent trophic levels (i.e. predominantly trophic interactions), while significant interactions among plant and carnivore functional groups, as well as horizontal interactions (i.e. interactions between functional groups of the same trophic level), showed rather inconsistent responses and were generally rarer. 4.?Reduced interaction diversity has the potential to decrease and destabilize ecosystem processes. Therefore, we conclude that the loss of basal producer species leads to more simple structured, less and more loosely connected species assemblages, which in turn are very likely to decrease ecosystem functioning, community robustness and tolerance to disturbance. Our results suggest that the functioning of the entire ecological community is critically linked to the diversity of its component plants species.     

B lymphocyte-typing for prediction of clinical response to rituximab

Introduction

The prediction of therapeutic response to rituximab in rheumatoid arthritis is desirable. We evaluated whether analysis of B lymphocyte subsets by flow cytometry would be useful to identify non-responders to rituximab ahead of time.

Methods

Fifty-two patients with active rheumatoid arthritis despite therapy with TNF-inhibitors were included in the national rituximab registry. DAS28 was determined before and 24 weeks after rituximab application. B cell subsets were analyzed by high-sensitive flow cytometry before and 2 weeks after rituximab administration. Complete depletion of B cells was defined as CD19-values below 0.0001 x10⁹ cells/liter.

Results

At 6 months 19 patients had a good (37%), 23 a moderate (44%) and 10 (19%) had no EULAR-response. The extent of B lymphocyte depletion in peripheral blood did not predict the success of rituximab therapy. Incomplete depletion was found at almost the same frequency in EULAR responders and non-responders. In comparison to healthy controls, non-responders had elevated baseline CD95⁺ pre-switch B cells, whereas responders had a lower frequency of plasmablasts.

Conclusions

The baseline enumeration of B lymphocyte subsets is still of limited clinical value for the prediction of response to anti-CD20 therapy. However, differences at the level of CD95+ pre switch B cells or plasmablasts were noticed with regard to treatment response. The criterion of complete depletion of peripheral B cells after rituximab administration did not predict the success of this therapy in rheumatoid arthritis.     

Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.     

A Variant In the Abo Gene Explains the Variation in Soluble E-Selectin Levels—Results from Dense Genotyping in Two Independent Populations

Background

Elevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.

Methodology/ Principal Findings

Data of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of −0.37 ng/ml (p = 1.87×10⁻¹⁰³) in KORA and −0.35 ng/ml (p = 5.11×10⁻⁸⁴) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.

Conclusions/ Significance

Our findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.     

Changes in the Prevalence,Treatment and Control of Hypertension in Germany? A Clinical-Epidemiological Study of 50.000 Primary Care Patients

Introduction

Medical societies have developed guidelines for the detection, treatment and control of hypertension (HTN). Our analysis assessed the extent to which such guidelines were implemented in Germany in 2003 and 2001.

Methods

Using standardized clinical diagnostic and treatment appraisal forms, blood pressure levels and patient questionnaires for 55,518 participants from the cross-sectional Targets and Essential Data for Commitment of Treatment (DETECT) study (2003) were analyzed. Physician’s diagnosis of hypertension (HTN_doc) was defined as coding hypertension in the clinical appraisal questionnaire. Alternative definitions used were physician’s diagnosis or the patient’s self-reported diagnosis of hypertension (HTN_doc,pat), physician’s or patient’s self-reported diagnosis or a BP measurement with a systolic BP≥140 mmHg and/or a diastolic BP≥90 (HTN_doc,pat,bp) and diagnosis according to the National Health and Nutrition Examination Survey (HTN_NHANES). The results were compared with the similar German HYDRA study to examine whether changes had occurred in diagnosis, treatment and adequate blood pressure control (BP below 140/90 mmHg) since 2001. Factors associated with pharmacotherapy and control were determined.

Results

The overall prevalence rate for hypertension was 35.5% according to HTN_doc and 56.0% according to NHANES criteria. Among those defined by NHANES criteria, treatment and control rates were 56.0% and 20.3% in 2003, and these rates had improved from 55.3% and 18.0% in 2001. Significant predictors of receiving antihypertensive medication were: increasing age, female sex, obesity, previous myocardial infarction and the prevalence of comorbid conditions such as coronary heart disease (CHD), hyperlipidemia and diabetes mellitus (DM). Significant positive predictors of adequate blood pressure control were CHD and antihypertensive medication. Inadequate control was associated with increasing age, male sex and obesity.

Conclusions

Rates of treated and controlled hypertension according to NHANES criteria in DETECT remained low between 2001 and 2003, although there was some minor improvement.     

Forisome performance in artificial sieve tubes

In the legume phloem, sieve element occlusion (SEO) proteins assemble into Ca(2+)-dependent contractile bodies. These forisomes presumably control phloem transport by forming reversible sieve tube plugs. This function, however, has never been directly demonstrated, and appears questionable as forisomes were reported to be too small to plug sieve tubes, and failed to block flow efficiently in artificial microchannels. Moreover, plugs of SEO-related proteins in Arabidopsis sieve tubes do not affect phloem translocation. We improved existing procedures for forisome isolation and storage, and found that the degree of Ca(2+)-driven deformation that is possible in forisomes of Vicia faba, the standard object of earlier research, has been underestimated substantially. Forisomes deform particularly strongly under reducing conditions and high sugar concentrations, as typically found in sieve tubes. In contrast to our previous inference, Ca(2+)-inducible forisome swelling certainly seems sufficient to plug sieve tubes. This conclusion was supported by 3D-reconstructions of forisome plugs in Canavalia gladiata. For a direct test, we built microfluidics chips with artificial sieve tubes. Using fluorescent dyes to visualize flow, we demonstrated the complete blockage of these biomimetic microtubes by Ca(2+)-induced forisome plugs, and concluded by analogy that forisomes are capable of regulating phloem flow in vivo.     

Selective survival of calretinin- and vasoactive-intestinal-peptide-containing nerve elements in human chagasic submucosa and mucosa

Chronic Chagas' disease is frequently characterized by massive myenteric neuron loss resulting in megacolon with severely and irreversibly disturbed motility. Here, we focused on two submucosal neuron populations, immunoreactive for calretinin (CALR) or somatostatin (SOM), and their respective mucosal nerve fibres in chagasic megacolon. Surgically removed megacolonic segments of seven chagasic patients were compared with seven age- and region-matched non-chagasic control segments. Evaluation included immunohistochemical triple-staining of cryosections for CALR, SOM and peripherin or for CALR and vasoactive intestinal peptide (VIP) and of submucosal whole-mounts for CALR, SOM and the pan-neuronal marker anti-HuC/D. Submucosal neuron counts in chagasic tissue revealed neuron numbers reduced to 51.2?% of control values. In cryosections, nerve fibre area measurements revealed 8.6?% nerve fibre per mucosal area in control segments, but this value decreased to 1.5?% in megacolonic segments. In both evaluations, a disproportionate decrease of SOM-reactive nerve elements was observed. The proportions of SOM-positive neurons related to the total neuron number declined to 2?% (control 10?%) and the proportion of SOM-reactive mucosal nerve fibres related to the whole mucosal area to 0.014?% (control 1.8?%)in chagasic tissue. The second set of cryosections revealed extensive colocalization of CALR with VIP in both surviving submucosal perikarya and mucosal nerve fibres. We suggest that VIP, a neuroprotective and neuroeffectory peptide typically contained in submucosal neurons, allows both the VIP-containing neurons to endure and the patients to survive by maintaining their mucosal barrier, despite the almost complete loss of colonic motility for decades.