Biomarkers for lysosomal storage disorders: identification and application as exemplified by chitotriosidase in Gaucher disease

A biomarker is an analyte that indicates the presence of a biological process linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing determinations of disease activity. In the case of lysosomal storage disorders (LSDs), metabolites or proteins specifically secreted by storage cells are good candidates for biomarkers. Potential clinical applications of biomarkers are found in improved diagnosis, monitoring of disease progression and assessment of therapeutic correction. These applications are illustrated by reviewing the use of plasma chitotriosidase in the clinical management of patients with Gaucher disease, the most common LSD. The ongoing debate on the value of biomarkers in patient management is addressed. Novel analytical methods have revolutionized the identification and measurement of biomarkers at the protein and metabolite level. Recent developments in biomarker discovery by proteomics are described and the future for biomarkers of LSDs is discussed. CONCLUSION: Besides direct applications for biomarkers in patient management, biomarker searches are likely to render new insights into pathophysiological mechanisms and metabolic adaptations, and may provide new targets for therapeutic intervention.     

Optimal measurement technic for the vasoconstrictor effect of corticosteroids. Comparative studies with reflection photometry and flow measurement

In 20 healthy male test subjects, a non-specific ointment base was applied to the back of the hand over 16 hours. Two days later, the same ointment base with 0.25% triamcinolone acetonide was once more applied to the back of the hand over 16 hours. The light reflection of the skin was measured by reflection photometry and the heat transport coefficient was measured fluvographically under the condition of the tourniquet test. The results show that the vasoconstrictor effect of triamcinolone acetonide is best detected by the reflection photometric measurements. In fluvographic measurement, the heat transport coefficient is most affected in maximal reactive hyperemia when the tourniquet has been removed. Application of the base led to a reduction of the blood flow and the water content of the skin after 16 hours, whereas the water content of the skin was unaffected in the presence of triamcinolone acetonide.     

Autosomal dominant Parkinson's disease in a large German pedigree

Brüggemann N, Külper W, Hagenah J, Bauer P, Pattaro C, Tadic V, Lohnau T, Winkler S, Tönnies H, Sprenger A, Pramstaller P, Rolfs A, Siebert R, Riess O, Vieregge P, Lohmann K, Klein C. Autosomal dominant Parkinson’s disease in a large German pedigree.
Acta Neurol Scand: 2012: 126: 129–137.
© 2011 John Wiley & Sons A/S. Objective – While several genes have been identified to cause Parkinson′s disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late‐onset autosomal dominant PD. Methods – Thirty‐eight family members of a five‐generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD‐causing genes and a genome‐wide linkage analysis were performed. Results – Late‐onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD‐causing genes. Genome‐wide linkage analysis suggested a putative disease gene in an 11.3‐Mb region on chromosome 7p15–21.1 with a multipoint LOD score of 2.0. Conclusions – The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late‐onset PD.     

Impact of dynamic bottom-up features and top-down control on the visual exploration of moving real-world scenes in hemispatial neglect

Patients with hemispatial neglect are severely impaired in orienting their attention to contralesional hemispace. Although motion is one of the strongest attentional cues in humans, it is still unknown how neglect patients visually explore their moving real-world environment. We therefore recorded eye movements at bedside in 19 patients with hemispatial neglect following acute right hemisphere stroke, 14 right-brain damaged patients without neglect and 21 healthy control subjects. Videos of naturalistic real-world scenes were presented first in a free viewing condition together with static images, and subsequently in a visual search condition. We analyzed number and amplitude of saccades, fixation durations and horizontal fixation distributions. Novel computational tools allowed us to assess the impact of different scene features (static and dynamic contrast, colour, brightness) on patients' gaze. Independent of the different stimulus conditions, neglect patients showed decreased numbers of fixations in contralesional hemispace (ipsilesional fixation bias) and increased fixation durations in ipsilesional hemispace (disengagement deficit). However, in videos left-hemifield fixations of neglect patients landed on regions with particularly high dynamic contrast. Furthermore, dynamic scenes with few salient objects led to a significant reduction of the pathological ipsilesional fixation bias. In visual search, moving targets in the neglected hemifield were more frequently detected than stationary ones. The top-down influence (search instruction) could neither reduce the ipsilesional fixation bias nor the impact of bottom-up features. Our results provide evidence for a strong impact of dynamic bottom-up features on neglect patients' scanning behaviour. They support the neglect model of an attentional priority map in the brain being imbalanced towards ipsilesional hemispace, which can be counterbalanced by strong contralateral motion cues. Taking into account the lack of top-down control in neglect patients, bottom-up stimulation with moving real-world stimuli may be a promising candidate for future neglect rehabilitation schemes.     

Do predictive mechanisms improve the angular vestibulo-ocular reflex in vestibular neuritis?

Recovery from vestibular neuritis (VN) is often incomplete which leads to persistent vestibular imbalance during rapid head movements. Patients with unilateral vestibular lesions have a larger gain of the horizontal vestibulo-ocular reflex during active compared to passive head movements. To test whether this gain increase is related to predictive mechanisms we studied 15 patients with VN and 14 control subjects during predictable and unpredictable passive horizontal head impulses in the light and darkness. The vestibulo-ocular reflex showed a significantly shorter latency and higher gain in the light for predictable head impulses towards the ipsilesional side. However, this effect is small and might contribute but cannot exclusively account for the gain increase during active head movements.     

Structural comparison of the external glycoproteins of human and simian immunodeficiency virus

The structural variability of the external glycoproteins of primate immunodeficiency viruses, has, so far, been investigated exclusively by sequence comparison of the respective proviral genomes. We have examined the structural relationship amount the external glycoproteins from three specific human immunodeficiency viruses (HIF-1, HIV-2), three specific simian immunodeficiency viruses from macaques (SIVmac) and three specific SIV from African green monkeys (SIVagm) by peptide mapping. Differences among glycoproteins were most pronounced between HIV-1 and SIVmac, as well as HIV-2. Two specific glycoproteins from independent SIVagm isolates were closely related to HIV-1, whereas the glycoprotein from a third SIVagm isolate was more similar to those of SIVmac and HIV-2. Our analysis reflects the classification of primate immunodeficiency viruses into three groups, the HIV-2 and SIVmac viruses, the green monkey isolates and HIV-1.     

Nomograms for the prediction of patient's plasma volume in plasma exchange therapy from height, weight, and hematocrit

The knowledge of plasma volume (PV) is a basic requirement for the standardization of plasma exchange therapy. PV has to be determined by calculation, as the measurement of PV before every plasma exchange is too cost- and time consuming. A known correlation with measured values results from calculation of plasma volume by means of patient's height and weight. But the present equations are only reliable at normal hematocrit. For this reason we modified the Retzlaff-equations and compared the validity of plasma volume predictions, calculated by these and own equations, with plasma volume measured by the 51Cr-method in 59 patients with pathological hematocrit. The correlation coefficient was 0.82 for men and 0.81 for women (2 0.001) with the modified Retzlaff-equations. On the average the relative error was -1.5% for all and 2.8% for fat and thin men. No significant improvement of accuracy was achieved with other equations. Thus, plasma volume can accurately be calculated from height, weight, and hematocrit with our modified Retzlaff-equations in patients with pathological hematocrit, even if they are very fat or thin. Nomograms for men and women were constructed in order to facilitate the calculation.