In vitro induction of functional allergen-specific CD4+ CD25high Treg cells in horses affected with insect bite hypersensitivity

BACKGROUND Insect bite hypersensitivity (IBH) is a recurrent allergic dermatitis of horses with similarities to human atopic eczema, caused by bites of insects of the genus Culicoides. Previous studies suggested a dysregulated T cell tolerance to Culicoides allergen in IBH-affected horses. OBJECTIVE We have investigated whether the suppressive function of CD4(+) CD25(high) cells is impaired in IBH-affected horses and possible ways to restore it. METHODS CD4(+) CD25(-) cells sorted from peripheral blood mononuclear cells (PBMC) were stimulated with irradiated autologous PBMC pulsed with Culicoides or tetanus toxoid as control antigen, in the presence of CD4(+) CD25(high) cells. Furthermore, Culicoides-specific CD4(+) CD25(high) regulatory cells were expanded or induced from CD4(+) CD25(-) cells in vitro in the presence of a combination of rIL-2 and rTGF-β1 (rIL-2/rTGF-β1) or of retinoic acid and rapamycin (RetA/Rapa). Proliferation was determined by [(3) H] thymidine incorporation and cytokine production measured by flow cytometry. RESULTS The ability of Culicoides- but not tetanus-stimulated CD4(+) CD25(high) cells to suppress proliferation of CD4(+) CD25(-) cells was significantly lower in IBH-affected horses (28%) than in healthy controls (86%). The decreased suppression in IBH-affected horses was associated with a significantly higher proportion of IL-4(+) cells and a lower percentage of FoxP3(+) IL-10(+) compared to controls. Addition of rIL-2/rTGF-β1 or of RetA/Rapa to Culicoides-stimulated CD4(+) CD25(high) cells from IBH-affected horses significantly increased the proportion of FoxP3(+) IL-10(+) cells. We also found that RetA/Rapa induced a more significant decrease in the frequency of IL-4(+) cells than rIL-2/rTGF-β1. Moreover, the suppressive activity of Culicoides-stimulated CD4(+) CD25(high) cells was significantly restored by both rIL-2/rTGF-β1and RetA/Rapa, albeit in an antigen-unspecific manner. In contrast, in vitro induced Culicoides-specific CD4(+) CD25(high) cells suppressed proliferation of CD4(+) CD25(-) cells in an antigen-specific manner. CONCLUSION AND CLINICAL RELEVANCE The in vitro induction of functional allergen-specific Treg cells in IBH-affected horses suggests a potential therapeutic use of these cells in allergy.

Age-related normal structural and functional ventricular values in cardiac function assessed by magnetic resonance

BACKGROUND The heart is subject to structural and functional changes with advancing age. However, the magnitude of cardiac age-dependent transformation has not been conclusively elucidated. METHODS This retrospective cardiac magnetic resonance (CMR) study included 183 subjects with normal structural and functional ventricular values. End systolic volume (ESV), end diastolic volume (EDV), and ejection fraction (EF) were obtained from the left and the right ventricle in breath-hold cine CMR. Patients were classified into four age groups (20-29, 30-49, 50-69, and ≥70 years) and cardiac measurements were compared using Pearson's rank correlation over the four different groups. RESULTS With advanced age a slight but significant decrease in ESV (r=-0.41 for both ventricles, P<0.001) and EDV (r=-0.39 for left ventricle, r=-0.35 for right ventricle, P<0.001) were observed associated with a significant increase in left (r=0.28, P<0.001) and right (r=0.27, P<0.01) ventricular EF reaching a maximal increase in EF of +8.4% (P<0.001) for the left and +6.1% (P<0.01) for the right ventricle in the oldest compared to the youngest patient group. Left ventricular myocardial mass significantly decreased over the four different age groups (P<0.05). CONCLUSIONS The aging process is associated with significant changes in left and right ventricular EF, ESV and EDV in subjects with no cardiac functional and structural abnormalities. These findings underline the importance of using age adapted values as standard of reference when evaluating CMR studies.

The course of radiographic loosening, pain and functional outcome around the first revision of a total hip arthroplasty

Background: The published data on pain and physical function before and after revision of total hip arthroplasty (THA) is scarce. The study reports the course and interrelationships of radiographic loosening, pain and physical function 5 year before and after a first revision THA. Methods: The study was based on the IDES-THA database. All patients with their first THA revision for aseptic loosening and a documented index surgery on the same side and at least one pre-revision and one post-revision follow-up were selected. Only patients with an intact contralateral hip joint (Charnley class-A) were included. Follow-ups within ±5.5 years around the revision time point were analyzed. Annual prevalences of radiographic component loosening and the non-desired outcomes (moderate/severe/intolerable pain, walking <30 minutes, hip flexion range <90°) were calculated. Results: Signs of radiographic component loosening started to increase about 4 years before revision surgery. Two years later, a sharp increase of painful hips from 15% to 80% in the revision year was observed. In the year after revision surgery, this rate dropped back to below 10%. Walking capacity started to noticeably deteriorate 3 years before revision and in the revision year about 65% of patients could not walk longer than 30 minutes. As opposed to pain, walking capacity did not recover to pre-revision levels and the best outcome was only reached two years post-revision. Hip flexion range had the slowest and least extent of deterioration (≈45% flexed <70° in the revision year) but with the best outcomes at only three years after revision surgery it took the longest to recover. Conclusion: Prevalence of radiological loosening signs and/or pain intensity follow an almost parallel course around the first revision of a THA for aseptic component loosening. This process begins about 4 years (radiographic loosening) before the actual revision surgery and intensifies about 2 years later (pain). It also involves walking capacity and hip range of motion. While pain levels go back to levels similar to those after primary surgery, range of motion and even more walking capacity remain moderately compromised.

Short-term Functional and Patient Outcome of the Bi-cruciate Stabilized Total Knee Replacement: Prospective Consecutive Case-series

Background: Total knee replacement is the gold standard treatment for patients suffering from advanced symptomatic knee osteoarthritis. The main goals of knee prosthetics are pain reduction and restoration of knee motion. The new prostheses on the market such as the bi-cruciate stabilized Journey knee implant, promise a reconstruction of total physiological function of the knee with physiological range of motion and therefore high patient satisfaction. Purpose: The aim of this study was to analyze the patient-based Knee Injury and Osteoarthritis Outcome Score (KOOS) outcome after total knee replacement with new physiological bi-cruciate stabilized Journey knee prosthesis. Study Design: Prospective, consecutive case-series. Patients: Ninety nine patients, who received bi-cruciate stabilized Journey total knee prosthesis between January 1st 2006 and May 31st 2012, were included in the study. A single surgeon operated all patients. There were 61.1% females and the overall average age was 68 years (range 41-83 years). Left knee was replaced in 55.6%. Methods: The patients filled in KOO’s questionnaire pre- and 1 year postoperative. Range of motion (ROM) was studied preoperatively and at 1-year follow-ups. The pre- and postoperative KOOS subscores and ROM were compared using the Wilcoxon signed rank test. Results: There are significant improvements of all KOOS subscores. Ninety percent of patients have reached the minimum clinically relevant 10 points in symptoms, 94.5% in pain, 94.5% in activities of daily living, 84.9% in sport and recreation, and 90% in knee related quality of life. Postoperative, the average passive ROM was 131° (range 110-145°) and the average active ROM 122° (range 105-135°). The highest correlation coefficients ROM and the KOOS were observed for the activity and pain subscores. Very low or no correlation was seen for the sport subscore. Conclusions: Bi-cruciate stabilized knee prosthetic offers a solid outcome 1 year postoperative based on the results measured with the KOOS evaluation questionnaire. The Patients showed a generalized improvement in all domains measured in the KOOS of minimally 35, and up to over 52 points, what can be described as statistically significant. Patients described the level of functionality close to double compared to the preoperative status.

Short-term functional outcome and premorbid adjustment in clinical high-risk patients. Results of the EPOS project

PURPOSE In patients with schizophrenia, premorbid psychosocial adjustment is an important predictor of functional outcome. We studied functional outcome in young clinical high-risk (CHR) patients and how this was predicted by their childhood to adolescence premorbid adjustment. METHODS In all, 245 young help-seeking CHR patients were assessed with the Premorbid Adjustment Scale, the Structured Interview for Prodromal Syndromes (SIPS) and the Schizophrenia Proneness Instrument (SPI-A). The SIPS assesses positive, negative, disorganised, general symptoms, and the Global Assessment of Functioning (GAF), the SPI-A self-experienced basic symptoms; they were carried out at baseline, at 9-month and 18-month follow-up. Transitions to psychosis were identified. In the hierarchical linear model, associations between premorbid adjustment, background data, symptoms, transitions to psychosis and GAF scores were analysed. RESULTS During the 18-month follow-up, GAF scores improved significantly, and the proportion of patients with poor functioning decreased from 74% to 37%. Poor premorbid adjustment, single marital status, poor work status, and symptoms were associated with low baseline GAF scores. Low GAF scores were predicted by poor premorbid adjustment, negative, positive and basic symptoms, and poor baseline work status. The association between premorbid adjustment and follow-up GAF scores remained significant, even when baseline GAF and transition to psychosis were included in the model. CONCLUSION A great majority of help-seeking CHR patients suffer from deficits in their functioning. In CHR patients, premorbid psychosocial adjustment, baseline positive, negative, basic symptoms and poor working/schooling situation predict poor short-term functional outcome. These aspects should be taken into account when acute intervention and long-term rehabilitation for improving outcome in CHR patients are carried out.

A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology

This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects.

Changes in cerebral hemodynamics and oxygenation induced by different speech tasks – an assessment by combining functional near‐infrared spectroscopy and capnography

Introduction In several studies, we found that during guided rhythmic speech exercises, a decrease in cerebral hemodynamics and oxygenation occurred as the result of a decrease in the partial pressure of carbon dioxide in the arterial blood (PaCO2) during speaking. To further explore the effect of PaCO2 variations on cerebral hemodynamics and oxygenation, the aim of the present study was to investigate the impact of spoken, inner and heard speech tasks on these parameters. Material and Methods Speech tasks included recitation or inner recitation or listening to hexameter, alliteration, prose, or performing mental arithmetic. The following physiological parameters were measured: tissue oxygen saturation (StO2) and absolute concentrations of oxyhemoglobin, deoxyhemoglobin, total hemoglobin (over the left and right anterior prefrontal cortex, using an ISS OxiplexTS frequency domain near-infrared spectrometer) and end-tidal CO2 (PETCO2; using Nellcor N1000 and Datex NORMOCAP capnographs). Statistical analysis was applied to the differences between baseline, 2 tasks, and 3 post-baseline periods. Data of 3 studies with 24, 7 and 29 healthy subjects, respectively, were combined, and linear regression analyses were calculated. Results Linear regression analyses revealed significant relations between changes in oxyhemoglobin, deoxyhemoglobin, total hemoglobin or StO2 and the participants’ age, the baseline PETCO2 or certain speech tasks. While hexameter verses affected changes during the tasks, alliteration verses only affected changes during the recovery phase. Discussion and Conclusion The observed effects in hemodynamics and oxygenation indicate a combination of neurovascular coupling (increased neuronal activity leading to an increase in the cerebral metabolic rate of oxygen resulting in an increase in cerebral flood flow/volume) and CO2 reactivity (increased breathing during speech tasks causing a decrease in PaCO2 leading to vasoconstriction and decrease in cerebral blood flow). The neurovascular coupling characteristics are task-dependent. References Scholkmann F, Gerber U, Wolf M, Wolf U. End-tidal CO2: An important parameter for a correct interpretation in functional brain studies using speech tasks. Neuroimage 2013;66:71-79. Scholkmann F, Wolf M, Wolf U. The effect of inner speech on arterial CO2, cerebral hemodynamics and oxygenation – A functional NIRS study. Adv Exp Med Biol 2013;789:81-87.

Functional and anatomical outcome of eyes with neovascular age-related macular degeneration treated with intravitreal ranibizumab following an exit strategy regimen.

AIMS To assess the functional and morphological outcome of eyes with neovascular AMD treated with intravitreal ranbizumab following an exit strategy treatment regime. METHODS The Bern treatment regime for neovascular AMD has a fixed injection schedule, even in the non-active stage of the disease. The regimen has been adapted from the PIER study treatment protocol. Eyes with non-active AMD will receive 4 injections in the first year, and 2 injections in the second year of follow-up before treatment stops. Patients that received ranibizumab for treatment and reached the exit criteria were identified, and charts were reviewed to assess functional and morphological outcome. RESULTS Only 2.6% of all patients (15 out of 575 patients) reached the exit criteria. Mean change in best corrected ETDRS visual acuity (VA) was 4.5±16.9 letters when comparing baseline VA to 4 weeks after the last injection (p=0.32). OCT mean foveal thickness was significantly thinner after last treatment (247.9±43.0 µm) compared to baseline (332.5±83.1 µm, p=0.002). The mean total number of ranibizumab injections was 15.6±8.0, and the mean total treatment period was 40.9±18.3 months. Twenty percent of eyes had geographic atrophy present at baseline versus 46.6% at the end of treatment. CONCLUSIONS Even with a fixed treatment regime and a defined treatment exit strategy, only a small percentage of patients reach exit criteria. Retinal thickness has been significantly reduced by repeated intravitreal ranibizumab injections, and geographic atrophy became more frequent.

Functional assessment of collaterals in the human coronary circulation.

The coronary collateral circulation is an alternative source of blood supply to a myocardial area jeopardized by the failure of the stenotic or occluded vessel to provide enough blood flow to this region. Until recently, only qualitative or semiqualitative methods have been available for the assessment of the coronary collateral circulation in humans, such as the patient's history of walk-through angina pectoris, the registration of intracoronary ECG signs for myocardial ischaemia or angina pectoris during coronary occlusion, or coronary angiographic classification (score 0-3) of collaterals. Studies of coronary wedge pressure measurements distal of a balloon-occluded coronary artery and the recent advent of ultrathin pressure and Doppler angioplasty guidewires have made it possible to obtain pressure or flow velocity data in remote vascular areas and, thus, to calculate functional variables for coronary collateral flow. Those coronary occlusive pressure- and flow velocity-derived parameters express collateral flow as a fraction of antegrade coronary flow during vessel patency of the collateral-receiving vessel. They are both interchangeable, and they have been validated in comparison to 'traditional' methods and against each other. The possibility of accurately measuring coronary collateral flow indices in humans undergoing coronary balloon angioplasty opens areas of investigation of the pathogenesis, pathophysiology and therapeutic promotion of the collateral circulation previously reserved for exclusively experimental studies. The purpose of this article is to review several clinically available methods for the functional characterization of the coronary collateral circulation.

When to see a doctor for common health problems: distribution patterns of functional health literacy across migrant populations in Switzerland

BACKGROUND Knowing when to seek professional help for health problems is considered an important aspect of health literacy. However, little is known about the distribution of help-seeking knowledge in the general population or specific subpopulations. METHODS We analysed data from the "Health Monitoring of the Swiss Migrant Population 2010" and used a short survey tool to study the distribution of help-seeking knowledge. We sampled members of four migrant groups (from Portugal, Turkey, Serbia and Kosovo; n = 2,614). Our tool contained 12 items that addressed common physical and psychological health problems. A total sum score measured help-seeking knowledge. Two sub-scores analysed knowledge related to potential overuse (minor symptoms) or potential underuse (major symptoms). We applied linear regression to show variations in help-seeking knowledge by age, sex, region of origin and length of stay. RESULTS Controlling for self-rated health, we found that region of origin, higher education, female gender and younger age were significantly associated with higher knowledge scores. CONCLUSIONS We present empirical evidence of unequal distribution of help-seeking knowledge across four migrant populations in Switzerland. Our findings contribute to current conceptual developments in health literacy, and provide starting points for future research.

Rivastigmine effects on EEG spectra and three-dimensional LORETA functional imaging in Alzheimer's disease

OBJECTIVE The objective of the study is to investigate the electrocortical and the global cognitive effects of 3 months rivastigmine medication in a group of mild to moderate Alzheimer's disease patients. MATERIALS AND METHODS Multichannel EEG and cognitive performances measured with the Mini Mental State Examination in a group of 16 patients with mild to moderate Alzheimer's Disease were collected before and 3 months after the onset of rivastigmine medication. RESULTS Spectral analysis of the EEG data showed a significant power decrease in the delta and theta frequency bands during rivastigmine medication, i.e., a shift of the power spectrum towards 'normalization'. Three-dimensional low resolution electromagnetic tomography (LORETA) functional imaging localized rivastigmine effects in a network that includes left fronto-parietal regions, posterior cingulate cortex, bilateral parahippocampal regions, and the hippocampus. Moreover, a correlation analysis between differences in the cognitive performances during the two recordings and LORETA-computed intracortical activity showed, in the alpha1 frequency band, better cognitive performance with increased cortical activity in the left insula. CONCLUSION The results point to a 'normalization' of the EEG power spectrum due to medication, and the intracortical localization of these effects showed an increase of cortical activity in frontal, parietal, and temporal regions that are well-known to be affected in Alzheimer's disease. The topographic convergence of the present results with the memory network proposed by Vincent et al. (J. Neurophysiol. 96:3517-3531, 2006) leads to the speculation that in our group of patients, rivastigmine specifically activates brain regions that are involved in memory functions, notably a key symptom in this degenerative disease.

Neurotologic and functional MRI findings in a patient with bilateral profound deafness having Brown-Vialetto-Van Leare syndrome

INTRODUCTION We report the first findings of functional magnetic resonance imaging of the auditory cortex in a young woman with a bilateral cochleovestibular deficit as first manifestation of Brown-Vialetto-Van Leare syndrome. The patient had no open speech discrimination, even with hearing aids, and is depending on lip reading for communication. METHODS To evaluate the possible efficiency of a cochlear implantation, we investigated hemodynamic responses within the central auditory pathways using an auditory functional magnetic resonance imaging paradigm. RESULTS Blood oxygen level-dependent correlates were detected bilaterally along the auditory pathways after exposure to intermittent clicking tone stimulation at 2 kHz. CONCLUSION These results suggest integrity of the central auditory pathways and represent a positive argument to propose a cochlear implantation with the aim to restore hearing.

Methylnitrosourea (MNU)-induced retinal degeneration and regeneration in the zebrafish: histological and functional characteristics.

Retinal degenerative diseases, e.g. retinitis pigmentosa, with resulting photoreceptor damage account for the majority of vision loss in the industrial world. Animal models are of pivotal importance to study such diseases. In this regard the photoreceptor-specific toxin N-methyl-N-nitrosourea (MNU) has been widely used in rodents to pharmacologically induce retinal degeneration. Previously, we have established a MNU-induced retinal degeneration model in the zebrafish, another popular model system in visual research. A fascinating difference to mammals is the persistent neurogenesis in the adult zebrafish retina and its regeneration after damage. To quantify this observation we have employed visual acuity measurements in the adult zebrafish. Thereby, the optokinetic reflex was used to follow functional changes in non-anesthetized fish. This was supplemented with histology as well as immunohistochemical staining for apoptosis (TUNEL) and proliferation (PCNA) to correlate the developing morphological changes. In summary, apoptosis of photoreceptors occurs three days after MNU treatment, which is followed by a marked reduction of cells in the outer nuclear layer (ONL). Thereafter, proliferation of cells in the inner nuclear layer (INL) and ONL is observed. Herein, we reveal that not only a complete histological but also a functional regeneration occurs over a time course of 30 days. Now we illustrate the methods to quantify and follow up zebrafish retinal de- and regeneration using MNU in a video-format.

Relationships between functional traits and inorganic nitrogen acquisition among eight contrasting European grass species

Backgrounds and Aims Leaf functional traits have been used as a basis to categoize plants across a range of resource-use specialization, from those that conserve available resources to those that exploit them. However, the extent to which the leaf functional traits used to define the resource-use strategies are related to root traits and are good indicators of the ability of the roots to take up nitrogen (N) are poorly known. This is an important question because interspecific differences in N uptake have been proposed as one mechanism by which species coexistence may be determined. This study therefore investigated the relationships between functional traits and N uptake ability for grass species across a range of conservative to exploitative resource-use strategies.Methods Root uptake of NH4+ and NO3-, and leaf and root functional traits were measured for eight grass species sampled at three grassland sites across Europe, in France, Austria and the UK. Species were grown in hydroponics to determine functional traits and kinetic uptake parameters (Imax and Km) under standardized conditions.Key Results Species with high specific leaf area (SLA) and shoot N content, and low leaf and root dry matter content (LDMC and RDMC, respectively), which are traits associated with the exploitative syndrome, had higher uptake and affinity for both N forms. No trade-off was observed in uptake between the two forms of N, and all species expressed a higher preference for NH4+.Conclusions The results support the use of leaf traits, and especially SLA and LDMC, as indicators of the N uptake ability across a broad range of grass species. The difficulties associated with assessing root properties are also highlighted, as root traits were only weakly correlated with leaf traits, and only RDMC and, to a lesser extent, root N content were related to leaf traits.

The impact of prolonged lower limb ischemia on amputation, mortality, and functional status: the FRIENDS registry.

BACKGROUND Peripheral artery disease (PAD) is a major cause of cardiovascular ischemic events and amputation. Knowledge gaps exist in defining and measuring key factors that predict these events. The objective of this study was to assess whether duration of limb ischemia would serve as a major predictor of limb and patient survival. METHODS The FReedom from Ischemic Events: New Dimensions for Survival (FRIENDS) registry enrolled consecutive patients with limb-threatening peripheral artery disease at a single tertiary care hospital. Demographic information, key clinical care time segments, functional status and use of revascularization, and pharmacotherapy data were collected at baseline, and vascular ischemic events, cardiovascular mortality, and all-cause mortality were recorded at 30 days and 1 year. RESULTS A total of 200 patients with median (interquartile range) age of 76 years (65-84 years) were enrolled in the registry. Median duration of limb ischemia was 0.75 days for acute limb ischemia (ALI) and 61 days for chronic critical limb ischemia (CLI). Duration of limb ischemia of <12, 12 to 24, and >24 hours in patients with ALI was associated with much higher rates of first amputation (P = .0002) and worse amputation-free survival (P = .037). No such associations were observed in patients with CLI. CONCLUSIONS For individuals with ischemic symptoms <14 days, prolonged limb ischemia is associated with higher 30-day and 1-year amputation, systemic ischemic event rates, and worse amputation-free survival. No such associations are evident for individuals with chronic CLI. These data imply that prompt diagnosis and revascularization might improve outcomes for patients with ALI.