Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor and Role of the Hypothalamic-Pituitary-Adrenal Axis

A previous study identified the peroxisome proliferator-activated receptor alpha (PPARalpha) activation biomarkers 21-steroid carboxylic acids 11beta-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11beta,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA). In the present study, the molecular mechanism and the metabolic pathway of their production were determined. The PPARalpha-specific time-dependent increases in HDOPA and 20alpha-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPARalpha induced hepatic FGF21, which caused increased neuropeptide Y and agouti-related protein mRNAs in the hypothalamus, stimulation of the agouti-related protein/neuropeptide Y neurons, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased adrenal cortex hyperplasia and corticosterone production, revealing a link between PPARalpha and the HPA axis in controlling energy homeostasis and immune regulation. Corticosterone was demonstrated as the precursor of 21-carboxylic acids both in vivo and in vitro. Under PPARalpha activation, the classic reductive metabolic pathway of corticosterone was suppressed, whereas an alternative oxidative pathway was uncovered that leads to the sequential oxidation on carbon 21 resulting in HDOPA. The latter was then reduced to the end product 20alpha-DHOPA. Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPARalpha resulted in the induction of Aldh3a2 and Akr1c18, both of which were confirmed as target genes through introduction of promoter luciferase reporter constructs into mouse livers in vivo. This study underscores the power of mass spectrometry-based metabolomics combined with genomic and physiologic analyses in identifying downstream metabolic biomarkers and the corresponding upstream molecular mechanisms.

Complexity of chronic asthma and chronic obstructive pulmonary disease: implications for risk assessment, and disease progression and control

Although assessment of asthma control is important to guide treatment, it is difficult since the temporal pattern and risk of exacerbations are often unpredictable. In this Review, we summarise the classic methods to assess control with unidimensional and multidimensional approaches. Next, we show how ideas from the science of complexity can explain the seemingly unpredictable nature of bronchial asthma and emphysema, with implications for chronic obstructive pulmonary disease. We show that fluctuation analysis, a method used in statistical physics, can be used to gain insight into asthma as a dynamic disease of the respiratory system, viewed as a set of interacting subsystems (eg, inflammatory, immunological, and mechanical). The basis of the fluctuation analysis methods is the quantification of the long-term temporal history of lung function parameters. We summarise how this analysis can be used to assess the risk of future asthma episodes, with implications for asthma severity and control both in children and adults.

An integral conservative gridding--algorithm using Hermitian curve interpolation

The problem of re-sampling spatially distributed data organized into regular or irregular grids to finer or coarser resolution is a common task in data processing. This procedure is known as 'gridding' or 're-binning'. Depending on the quantity the data represents, the gridding-algorithm has to meet different requirements. For example, histogrammed physical quantities such as mass or energy have to be re-binned in order to conserve the overall integral. Moreover, if the quantity is positive definite, negative sampling values should be avoided. The gridding process requires a re-distribution of the original data set to a user-requested grid according to a distribution function. The distribution function can be determined on the basis of the given data by interpolation methods. In general, accurate interpolation with respect to multiple boundary conditions of heavily fluctuating data requires polynomial interpolation functions of second or even higher order. However, this may result in unrealistic deviations (overshoots or undershoots) of the interpolation function from the data. Accordingly, the re-sampled data may overestimate or underestimate the given data by a significant amount. The gridding-algorithm presented in this work was developed in order to overcome these problems. Instead of a straightforward interpolation of the given data using high-order polynomials, a parametrized Hermitian interpolation curve was used to approximate the integrated data set. A single parameter is determined by which the user can control the behavior of the interpolation function, i.e. the amount of overshoot and undershoot. Furthermore, it is shown how the algorithm can be extended to multidimensional grids. The algorithm was compared to commonly used gridding-algorithms using linear and cubic interpolation functions. It is shown that such interpolation functions may overestimate or underestimate the source data by about 10-20%, while the new algorithm can be tuned to significantly reduce these interpolation errors. The accuracy of the new algorithm was tested on a series of x-ray CT-images (head and neck, lung, pelvis). The new algorithm significantly improves the accuracy of the sampled images in terms of the mean square error and a quality index introduced by Wang and Bovik (2002 IEEE Signal Process. Lett. 9 81-4).

Spatial cognition, body representation and affective processes: the role of vestibular information beyond ocular reflexes and control of posture

A growing number of studies in humans demonstrate the involvement of vestibular information in tasks that are seemingly remote from well-known functions such as space constancy or postural control. In this review article we point out three emerging streams of research highlighting the importance of vestibular input: (1) Spatial Cognition: Modulation of vestibular signals can induce specific changes in spatial cognitive tasks like mental imagery and the processing of numbers. This has been shown in studies manipulating body orientation (changing the input from the otoliths), body rotation (changing the input from the semicircular canals), in clinical findings with vestibular patients, and in studies carried out in microgravity. There is also an effect in the reverse direction; top-down processes can affect perception of vestibular stimuli. (2) Body Representation: Numerous studies demonstrate that vestibular stimulation changes the representation of body parts, and sensitivity to tactile input or pain. Thus, the vestibular system plays an integral role in multisensory coordination of body representation. (3) Affective Processes and Disorders: Studies in psychiatric patients and patients with a vestibular disorder report a high comorbidity of vestibular dysfunctions and psychiatric symptoms. Recent studies investigated the beneficial effect of vestibular stimulation on psychiatric disorders, and how vestibular input can change mood and affect. These three emerging streams of research in vestibular science are—at least in part—associated with different neuronal core mechanisms. Spatial transformations draw on parietal areas, body representation is associated with somatosensory areas, and affective processes involve insular and cingulate cortices, all of which receive vestibular input. Even though a wide range of different vestibular cortical projection areas has been ascertained, their functionality still is scarcely understood.

Total disc arthroplasty versus anterior cervical interbody fusion: use of the Spine Tango registry to supplement the evidence from randomized control trials.

BACKGROUND CONTEXT Several randomized controlled trials (RCTs) have compared patient outcomes of anterior (cervical) interbody fusion (AIF) with those of total disc arthroplasty (TDA). Because RCTs have known limitations with regard to their external validity, the comparative effectiveness of the two therapies in daily practice remains unknown. PURPOSE This study aimed to compare patient-reported outcomes after TDA versus AIF based on data from an international spine registry. STUDY DESIGN AND SETTING A retrospective analysis of registry data was carried out. PATIENT SAMPLE Inclusion criteria were degenerative disc or disc herniation of the cervical spine treated by single-level TDA or AIF, no previous surgery, and a Core Outcome Measures Index (COMI) completed at baseline and at least 3 months' follow-up. Overall, 987 patients were identified. OUTCOME MEASURES Neck and arm pain relief and COMI score improvement were the outcome measures. METHODS Three separate analyses were performed to compare TDA and AIF surgical outcomes: (1) mimicking an RCT setting, with admission criteria typical of those in published RCTs, a 1:1 matched analysis was carried out in 739 patients; (2) an analysis was performed on 248 patients outside the classic RCT spectrum, that is, with one or more typical RCT exclusion criteria; (3) a subgroup analysis of all patients with additional follow-up longer than 2 years (n=149). RESULTS Matching resulted in 190 pairs with an average follow-up of 17 months that had no residual significant differences for any patient characteristics. Small but statistically significant differences in outcome were observed in favor of TDA, which are potentially clinically relevant. Subgroup analyses of atypical patients and of patients with longer-term follow-up showed no significant differences in outcome between the treatments. CONCLUSIONS The results of this observational study were in accordance with those of the published RCTs, suggesting substantial pain reduction both after AIF and TDA, with slightly greater benefit after arthroplasty. The analysis of atypical patients suggested that, in patients outside the spectrum of clinical trials, both surgical interventions appeared to work to a similar extent to that shown for the cohort in the matched study. Also, in the longer-term perspective, both therapies resulted in similar benefits to the patients.