Steady-state function of the ubiquitous mammalian Na/H exchanger (NHE1) in relation to dimer coupling models with 2Na/2H stoichiometry

We describe the steady-state function of the ubiquitous mammalian Na/H exchanger (NHE)1 isoform in voltage-clamped Chinese hamster ovary cells, as well as other cells, using oscillating pH-sensitive microelectrodes to quantify proton fluxes via extracellular pH gradients. Giant excised patches could not be used as gigaseal formation disrupts NHE activity within the patch. We first analyzed forward transport at an extracellular pH of 8.2 with no cytoplasmic Na (i.e., nearly zero-trans). The extracellular Na concentration dependence is sigmoidal at a cytoplasmic pH of 6.8 with a Hill coefficient of 1.8. In contrast, at a cytoplasmic pH of 6.0, the Hill coefficient is <1, and Na dependence often appears biphasic. Results are similar for mouse skin fibroblasts and for an opossum kidney cell line that expresses the NHE3 isoform, whereas NHE1(-/-) skin fibroblasts generate no proton fluxes in equivalent experiments. As proton flux is decreased by increasing cytoplasmic pH, the half-maximal concentration (K(1/2)) of extracellular Na decreases less than expected for simple consecutive ion exchange models. The K(1/2) for cytoplasmic protons decreases with increasing extracellular Na, opposite to predictions of consecutive exchange models. For reverse transport, which is robust at a cytoplasmic pH of 7.6, the K(1/2) for extracellular protons decreases only a factor of 0.4 when maximal activity is decreased fivefold by reducing cytoplasmic Na. With 140 mM of extracellular Na and no cytoplasmic Na, the K(1/2) for cytoplasmic protons is 50 nM (pH 7.3; Hill coefficient, 1.5), and activity decreases only 25% with extracellular acidification from 8.5 to 7.2. Most data can be reconstructed with two very different coupled dimer models. In one model, monomers operate independently at low cytoplasmic pH but couple to translocate two ions in "parallel" at alkaline pH. In the second "serial" model, each monomer transports two ions, and translocation by one monomer allosterically promotes translocation by the paired monomer in opposite direction. We conclude that a large fraction of mammalian Na/H activity may occur with a 2Na/2H stoichiometry.

Rapid estimation of cartilage T2 based on double echo at steady state (DESS) with 3 Tesla

The double-echo-steady-state (DESS) sequence generates two signal echoes that are characterized by a different contrast behavior. Based on these two contrasts, the underlying T2 can be calculated. For a flip-angle of 90 degrees , the calculated T2 becomes independent of T1, but with very low signal-to-noise ratio. In the present study, the estimation of cartilage T2, based on DESS with a reduced flip-angle, was investigated, with the goal of optimizing SNR, and simultaneously minimizing the error in T2. This approach was validated in phantoms and on volunteers. T2 estimations based on DESS at different flip-angles were compared with standard multiecho, spin-echo T2. Furthermore, DESS-T2 estimations were used in a volunteer and in an initial study on patients after cartilage repair of the knee. A flip-angle of 33 degrees was the best compromise for the combination of DESS-T2 mapping and morphological imaging. For this flip angle, the Pearson correlation was 0.993 in the phantom study (approximately 20% relative difference between SE-T2 and DESS-T2); and varied between 0.429 and 0.514 in the volunteer study. Measurements in patients showed comparable results for both techniques with regard to zonal assessment. This DESS-T2 approach represents an opportunity to combine morphological and quantitative cartilage MRI in a rapid one-step examination.

A Model to quantify Disease state based on the ayurvedic concept of Tridosa

The ancient Indian system of Ayurveda revolves around the concept of tridosha namely vata, pitta and kapha. The disturbance in the steady state of these three factors is said to be the starting point of the development of diseases. Even though the diseases and their associated symptoms are well- described in the medical system, no mention is directly made in the basic texts about the quantification. We offer here a specific protocol to quantify a disease in terms of ayurvedic principles

Shifted Coupling of EEG Driving Frequencies and fMRI Resting State Networks in Schizophrenia Spectrum Disorders

INTRODUCTION: The cerebral resting state in schizophrenia is altered, as has been demonstrated separately by electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) resting state networks (RSNs). Previous simultaneous EEG/fMRI findings in healthy controls suggest that a consistent spatiotemporal coupling between neural oscillations (EEG frequency correlates) and RSN activity is necessary to organize cognitive processes optimally. We hypothesized that this coupling is disorganized in schizophrenia and related psychotic disorders, in particular regarding higher cognitive RSNs such as the default-mode (DMN) and left-working-memory network (LWMN). METHODS: Resting state was investigated in eleven patients with a schizophrenia spectrum disorder (n = 11) and matched healthy controls (n = 11) using simultaneous EEG/fMRI. The temporal association of each RSN to topographic spectral changes in the EEG was assessed by creating Covariance Maps. Group differences within, and group similarities across frequencies were estimated for the Covariance Maps. RESULTS: The coupling of EEG frequency bands to the DMN and the LWMN respectively, displayed significant similarities that were shifted towards lower EEG frequencies in patients compared to healthy controls. CONCLUSIONS: By combining EEG and fMRI, each measuring different properties of the same pathophysiology, an aberrant relationship between EEG frequencies and altered RSNs was observed in patients. RSNs of patients were related to lower EEG frequencies, indicating functional alterations of the spatiotemporal coupling. SIGNIFICANCE: The finding of a deviant and shifted coupling between RSNs and related EEG frequencies in patients with a schizophrenia spectrum disorder is significant, as it might indicate how failures in the processing of internal and external stimuli, as commonly seen during this symptomatology (i.e. thought disorders, hallucinations), arise.

Frequency-domain source localization shows state-dependent diazepam effects in 47-channel EEG

The topic of this study was to evaluate state-dependent effects of diazepam on the frequency characteristics of 47-channel spontaneous EEG maps. A novel method, the FFT-Dipole-Approximation (Lehmann and Michel, 1990), was used to study effects on the strength and the topography of the maps in the different frequency bands. Map topography was characterized by the 3-dimensional location of the equivalent dipole source and map strength was defined as the spatial standard deviation (the Global Field Power) of the maps of each frequency point. The Global Field Power can be considered as a measure of the amount of energy produced by the system, while the source location gives an estimate of the center of gravity of all sources in the brain that were active at a certain frequency. State-dependency was studied by evaluating the drug effects before and after a continuous performance task of 25 min duration. Clear interactions between drug (diazepam vs. placebo) and time after drug intake (before and after the task) were found, especially in the inferior-superior location of the dipole sources. It supports the hypothesis that diazepam, like other drugs, has different effects on brain functions depending on the momentary functional state of the brain. In addition to the drug effects, clearly different source locations and Global Field Power were found for the different frequency bands, replicating earlier reports (Michel et al., 1992).

State of the science on controversial topics: missing maxillary lateral incisors - a report of the Angle Society of Europe 2012 meeting

BACKGROUND The optimal long-term management of the congenitally missing maxillary lateral incisor continues to cause controversy within the specialty. The Angle Society of Europe meeting 2012 dedicated a day to address some of the current controversies relating to the management of these missing lateral incisors. FINDINGS The format of the day consisted of morning presentations and afternoon breakout sessions to discuss a variety of questions related to the management of missing lateral incisors. CONCLUSIONS The consensus viewpoint from this day was that the care of patients with congenitally missing lateral incisors is best achieved through a multi-disciplinary approach. The current evidence base is weak, and further well-designed, prospective trials are needed.

State of the science on controversial topics: orthodontic therapy and gingival recession (a report of the Angle Society of Europe 2013 meeting)

BACKGROUND Controversy exists in the literature between the role of orthodontic treatment and gingival recession. Whilst movement of teeth outside the alveolar bone has been reported as a risk factor for gingival recession, others have found no such association. FINDINGS The Angle Society of Europe devoted a study day to explore the evidence surrounding these controversies. The aim of the day was for a panel of experts to evaluate the current evidence base in relation to either the beneficial or detrimental effects of orthodontic treatment on the gingival tissue. CONCLUSIONS There remains a relatively weak evidence base for the role of orthodontic treatment and gingival recession and thus a need to undertake a risk assessment and appropriate consent prior to the commencement of treatment. In further prospective, well designed trials are needed.

Standardized Performance Analysis (SPA) Summary for 1999-2000 Veterinary Medicine Students

Nine Iowa State University veterinary medical students completed SPA records on herds from Iowa, North Dakota and South Dakota. The Iowa herds were included in the SPA summary for Iowa, but the six North and South Dakota herds were summarized separately. These six herds had an average herd size of 371 cows and had a financial return to capital, labor and management of $175 per cow. Total financial cost per cow averaged $286 for these herds with a range of $211 to $388. Feed utilized averaged 4,442 pounds of dry matter per cow and the average pounds of calf produced per exposed female was 506 pounds.

Vordere Kreuzband-OP-Technik: «State of the Art» und Zukunft

Die Behandlung der vorderen Kreuzbandverletzung stellt die Chirurgie seit vielen Jahren vor grosse Herausforderungen. Die Geschichte der Kreuzbandchirurgie ist im Wesentlichen geprägt von der Suche nach dem perfekten Transplantat und dem operativen Fortschritt. In diesem Übersichtssartikel werden die aktuellen chirurgischen Strategien erörtert und ein Blick in die Zukunft gewagt.

A Targeted Survey for Scrapie in Jos Plateau State, Nigeria

Scrapie, a disease of sheep and goats with a progressive course and fatal outcome, has not been identified in Nigeria. Anecdotal scrapie reports by livestock workers abound. Livestock diseases like scrapie form huddles in livestock economics of countries. For 8 months we surveyed for scrapie targeting emergency/casualty slaughter sheep and goats in Jos, Nigeria. We clinically examined 510 sheep and 608 goats of local breeds, aged from 12 months to 5 years. In total 31 (5.10%) goats and no sheep were clinically suspicious for scrapie. Caudal brainstem tissues of suspect animals collected postmortem were analyzed for the disease specific form of the prion protein, PrPSc, using Bio-Rad’s TeSeE ELISA rapid test kit. No sample was positive for scrapie. Fluorescent antibody test for rabies and H&E staining on samples were carried out for differential diagnosis. These showed no pathological lesions indicative for neurological disease. While our findings do not exclude the presence of scrapie in Jos, we demonstrate that targeted sampling of small ruminants for neuroinfectious disease is feasible in developing countries, pointing to the possibility of implementing such a monitoring scheme in Nigeria to prevent economic losses in small ruminant livestock as scrapie caveats from endemic countries have shown.

Using state variables to model the response of tumour cells to radiation and heat: a novel multi-hit-repair approach

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.