Stated patient preferences for overnight at-home diagnostic assessment of sleep disorders.

PURPOSE: The diagnostic workup for assessment of sleep disorders commonly involves overnight testing to assess sleep patterns and pathological events. So far, little is known about preferences for provision of home sleep tests to patients with sleep disorders. This study aims to close this gap by eliciting preferences for home sleep testing using a discrete choice experiment (DCE). METHODS: A DCE with seven attributes of at-home sleep testing and three levels per attribute was developed using a fractional factorial design. Patients with and without previous sleep testing experience were recruited from two large sleep centers in Germany. Coefficients for attribute levels were calculated using a conditional logit model to estimate their influence on choice decisions and calculate the relative importance of each attribute. RESULTS: 305 patients (54.5 ± 13,1 years, 65.3% male) were enrolled, and 288 surveys with complete data included for analysis. Attributes with greatest relevance were Waiting time to discuss sleep study results; Waiting time to conduct sleep study, and Sleep quality during measurement. Of lowest importance was Diagnostic accuracy of sleep study, followed by Effort to apply sleep study device. Significant heterogeneity in choice behavior was found, including differences by gender, willingness-to-pay for sleep studies, and previous experience with sleep studies. Preferred location for conducting sleep testing was at-home in 50.7% and in-lab in 46.9%. CONCLUSIONS: Preferences and relative importance of home sleep test attributes vary among different subgroups. Considering those preferences can be important for clinicians and policymakers when designing care pathways and planning of testing policies for sleep disorders.

Patterns of invasive ctenophore Mnemiopsis leidyi distribution and variability in different recipient environments of the Eurasian seas: A review.

Harmful invader ctenophore Mnemiopsis leidyi's expansions in the Eurasian Seas, its spatio-temporal population dynamics depending on environmental conditions in recipient habitats have been synthesized. M. leidyi found suitable temperature, salinity and productivity conditions in the temperate and subtropical environments of the semi-enclosed seas, in the coastal areas of open basins and in closed water bodies, where it created autonomous populations. M. leidyi changes its phenology depending on seasonal temperature regime in different environments. We assessed ranges of sea surface temperature, sea surface salinity and sea surface chlorophyll values, sufficient for M. leidyi general occurrence and reproduction based on comprehensive long-term datasets, contributed by co-authors. This assessment revealed that there are at least two eco-types (Southern and Northern) in the recipient seas of Eurasia with features specific for their donor areas. The range of thresholds for M. leidyi establishment, occurrence and life cycle in both eco-types depends on variability of environmental parameters in their native habitats.

Establishment of a clinically relevant large animal model to assess the healing of metaphyseal bone.

Despite the high incidence of metaphyseal bone fractures in patients, the mechanisms underlying the healing processes are poorly understood due to the lack of suitable experimental animal models. Hence, the present study was conducted to establish and characterise a clinically relevant large-animal model for metaphyseal bone healing. Six female adult Merino sheep underwent full wedge-shaped osteotomy at the distal left femur metaphysis. The osteotomy was stabilised internally with a customised anatomical locking titanium plate that allowed immediate post-operative full-weight bearing. Bone healing was evaluated at 12 weeks post-fracture relative to the untouched right femur. Histological and quantitative micro-computed tomography results revealed an increased mineralised bone mass with a rich bone microarchitecture. New trabeculae healed by direct intramembranous ossification, without callus and cartilaginous tissue formation. Stiffness at the cortical and trabecular regions was comparable in both groups. Functional morphological analysis of the osteocyte lacunae revealed regularly arranged spherically shaped lacunae along with the canalicular network. Bone surface biochemical analysis using time-of-flight secondary-ion mass spectrometry showed high and homogeneously distributed levels of calcium and collagenous components. Ultrastructure imaging of the new trabeculae revealed a characteristic parallel arrangement of the collagen fibrils, evenly mineralised by the dense mineral substance. The specialised bone cells were also characterised by their unique structural features. Bone remodelling in the fractured femur was evident in the higher expression levels of prominent bone formation and resorption genes. In conclusion, the novel metaphyseal fracture model is beneficial for studying healing and treatment options for the enhancement of metaphyseal bone defects.

Differences in expression of Wnt antagonist Dkk1 in healthy versus pathological bone samples.

Wnt/ß-catenin signalling components was shown to affect bone cells function including chondrocytes.Secreted Dkk1, a potent osteogenesis inhibiting factor mediates bone loss in diseased bones by suppressing the biological actions of Wnt proteins. In addition, increased Dkk1 signalling inhibits chondrogenesis in new bone formation. Recent findings also show there exists a cross-talk between the chondrocytes and the cells of the osteoblast lineage, which are the most affected cell types in muskuloskeletal disorders. This study investigated whether spatial expression of Dkk1 is confined to only osteoblasts, osteocytes or chondrocytes. The second objective was to detect a difference in the Dkk1 expression pattern in healthy subjects when compared to pathological state. To elucidate the cell specificity of Dickkopf-1 (Dkk1) in healthy bones, samples from female Sprague-Dawley rats were tested against two different antibodies with the two most widely accepted visualization system (ABC and Envision). The findings show Dkk1 specificity predominantly for osteoblasts, chondrocytes and osteocytes depending upon the antibody used. In addition, Dkk1 expression was evaluated in different cells of human osteoarthritis (OA) and rheumatoid arthritis (OA) patients. Its overexpression in pathologic state also suggests the role of Dkk1 in bone formation. This is scientifically and clinically important in studying the effect of Dkk1 in bone healing and in designing treatments for patients with compromised bone status. Taking into consideration the paradigm that cartilage and subchondral bone behave as an interconnected functional unit, normalization of cell behaviour in one compartment may have benefits in both tissues.

Intracellular proliferation of S. aureus in osteoblasts and effects of rifampicin and gentamicin on S. aureus intracellular proliferation and survival.

Staphylococcus aureus is the most clinically relevant pathogen regarding implant-associated bone infection and its capability to invade osteoblasts is well known. The aim of this study was to investigate firstly whether S. aureus is not only able to invade but also to proliferate within osteoblasts, secondly to delineate the mechanism of invasion and thirdly to clarify whether rifampicin or gentamicin can inhibit intracellular proliferation and survival of S. aureus. The SAOS-2 osteoblast-like cell line and human primary osteoblasts were infected with S. aureus EDCC5055 and S. aureus Rosenbach 1884. Both S. aureus strains were able to invade efficiently and to proliferate within human osteoblasts. Immunofluorescence microscopy showed intracellular invasion of S. aureus and transmission electron microscopy images could demonstrate bacterial division as a sign of intracellular proliferation as well as cytosolic bacterial persistence. Cytochalasin D, the major actin depolymerisation agent, was able to significantly reduce S. aureus invasion, suggesting that invasion was enabled by promoting actin rearrangement at the cell surface. 7.5 µg/mL of rifampicin was able to inhibit bacterial survival in SAOS-2 cells with almost complete elimination of bacteria after 4 h. Gentamicin could also kill intracellular S. aureus in a dose-dependent manner, an effect that was significantly lower than that observed using rifampicin. In conclusion, S. aureus is not only able to invade but also to proliferate in osteoblasts. Invasion seems to be associated with actin rearrangement at the cell surface. Rifampicin is effective in intracellular eradication of S. aureus whereas gentamicin only poorly eliminates intracellularly replicating bacteria.

Anaerobic metabolism at thermal extremes: a metabolomic test of the oxygen limitation hypothesis in an aquatic insect.

Thermal limits in ectotherms may arise through a mismatch between supply and demand of oxygen. At higher temperatures, the ability of their cardiac and ventilatory activities to supply oxygen becomes insufficient to meet their elevated oxygen demand. Consequently, higher levels of oxygen in the environment are predicted to enhance tolerance of heat, whereas reductions in oxygen are expected to reduce thermal limits. Here, we extend previous research on thermal limits and oxygen limitation in aquatic insect larvae and directly test the hypothesis of increased anaerobic metabolism and lower energy status at thermal extremes. We quantified metabolite profiles in stonefly nymphs under varying temperatures and oxygen levels. Under normoxia, the concept of oxygen limitation applies to the insects studied. Shifts in the metabolome of heat-stressed stonefly nymphs clearly indicate the onset of anaerobic metabolism (e.g., accumulation of lactate, acetate, and alanine), a perturbation of the tricarboxylic acid cycle (e.g., accumulation of succinate and malate), and a decrease in energy status (e.g., ATP), with corresponding decreases in their ability to survive heat stress. These shifts were more pronounced under hypoxic conditions, and negated by hyperoxia, which also improved heat tolerance. Perturbations of metabolic pathways in response to either heat stress or hypoxia were found to be somewhat similar but not identical. Under hypoxia, energy status was greatly compromised at thermal extremes, but energy shortage and anaerobic metabolism could not be conclusively identified as the sole cause underlying thermal limits under hyperoxia. Metabolomics proved useful for suggesting a range of possible mechanisms to explore in future investigations, such as the involvement of leaking membranes or free radicals. In doing so, metabolomics provided a more complete picture of changes in metabolism under hypoxia and heat stress.

What can molecular pathology offer for optimal decision making?

In recent years, colorectal cancer (CRC), once a uniform disease with well-understood carcinogenesis, has been divided into at least five different subgroups with distinct precursor lesions, pathways of carcinogenesis, morphological, and molecular characteristics. Moreover, new therapeutic concepts with 'targeted' substances have added to the complexity of the management of CRC patients. The clinical value of biomarkers in advanced CRC is indisputable ever since activating mutations of the KRAS oncogene have been shown to predict resistance to anti-epidermal growth factor receptor antibodies. Prognostic biomarkers predicting patient outcomes and predictive biomarkers forecasting response to a certain therapy may help us to improve therapeutic agent selection and patient management with the ultimate goal of maximizing the benefit of treatment and minimizing toxicity. Biomarkers with known implications in advanced CRC will be discussed in this paper.

[Impact of TGF-beta1 antisense on collagen-binding integrins in keloid]. / TGF-beta1-Antisense beeinflusst kollagenbindende Integrine im Keloid.

BACKGROUND: The treatment of keloids remains challenging due to sparse knowledge about the pathogenesis of this disease. Transforming growth factor (TGF)-beta1 plays a central role in keloid formation. Cell-matrix communication is controlled by integrins, the expression of which can be regulated by TGF-beta1. METHODS: Using immunohistochemistry we compared expression patterns of alpha1beta1, alpha2beta1 und alpha3beta1 in normal skin and keloid tissue. Secondly, the effect of TGF-beta1-antisense after 48 h and 72 h incubation in a keloid-derived fibroblast monolayer was analyzed by means of reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: alpha1beta1 and alpha2beta1 were highly expressed in keloid fibroblasts. Incubation with TGF-beta1-antisense lead to a reduction on protein level. RT-PCR demonstrated an increase of all alpha subunits, while on an mRNA level a decrease of the subunit beta1 could be observed. CONCLUSION: Integrin expression is directly modulated by TGF-beta1. An abnormal response in the keloid as a result of an altered TGF-beta1 pathway could be a key element to understanding the development of keloids.

Simultaneous delta15N, delta13C and delta34S measurements of low-biomass samples using a technically advanced high sensitivity elemental analyzer connected to an isotope ratio mass spectrometer.

Conventional simultaneous CNS stable isotope abundance measurements of solid samples usually require high sample amounts, up to 1 mg carbon, to achieve exact analytical results. This rarely used application is often impaired by high C:S element ratios when organic samples are analyzed and problems such as incomplete conversion into sulphur dioxide occur during analysis. We introduce, as a technical innovation, a high sensitivity elemental analyzer coupled to a conventional isotope ratio mass spectrometer, with which CNS-stable isotope ratios can be determined simultaneously in samples with low carbon content (<40 microg C corresponding to approximately 100 microg dry weight). The system includes downsized reactors, a temperature program-controlled gas chromatography (GC) column and a cryogenic trap to collect small amounts of sulphur dioxide. This modified application allows for highly sensitive measurements in a fully automated operation with standard deviations better than +/-0.47 per thousand for delta15N and delta34S and +/-0.12 per thousand for delta13C (n = 127). Samples collected from one sampling site in a Baltic fjord within a short time period were measured with the new system to get a first impression of triple stable isotope signatures. The results confirm the potential of using delta34S as a stable isotope tracer in combination with delta15N and delta13C measurements to improve discrimination of food sources in aquatic food webs.

Relevance of laser irradiance threshold in the induction of alkaline phosphatase in human osteoblast cultures.

Induction of matrix synthesis by low-level laser has been demonstrated extensively. However, the question of dose- or power intensity-dependency is under-investigated. To address this issue we chose human osteoblast cell cultures and measured their alkaline phosphatase (ALP) activity after laser irradiation. The cell cultures were irradiated periodically by 690 nm radiation via optical transmission fiber-based laser needles, reaching into the culture dishes. The osteoblasts showed no induction of ALP activity when we used a single laser needle stimulation with a laser irradiance of 51 mW/cm(2), an increase of approximately 43% at 102 mW/cm(2) irradiance (two needles per well) and a ninefold increase at 204 mW/cm(2) irradiance (four needles per well), leaving the temperature of the culture medium unaffected. We concluded that the osteoblastic response in ALP activity to a laser stimulus shows a logarithmic relationship, with a distinct threshold, rather than a linear dose-dependency. Secondly, the laser irradiance, rather than the dose, is relevant for the impact of the laser.

Increasing the sensitivity of delta13C and delta15N abundance measurements by a high sensitivity elemental analyzer connected to an isotope ratio mass spectrometer.

A common elemental analyzer system connected to a temperature-controlled gas chromatography (GC) column and coupled to an isotope ratio mass spectrometer was improved to decrease the determination limit for a simultaneous stable isotope ratio measurement of nitrogen and carbon dioxide. The additional use of a special ashtray system to collect the combustion residuals permitted more time-efficient work. These modifications to the elemental analyzer allowed precise measurements to be made down to 1.5 microg nitrogen and 10 microg carbon for stable isotope analysis. Low system background values and an acceptable signal-to-noise ratio have made an additional blank correction for these low sample measurements unnecessary. We provide a precision of this stable isotope analysis for lowest amounts of 1.2-2 microg nitrogen with a standard deviation of +/-0.496 per thousand (n = 27) and for 8.2-15 microg carbon with a standard deviation of +/-0.257 per thousand (n = 31) across different sample runs under stipulated conditions. This application can be established in an automatic mode without cryofocusing procedures.

Spring bloom succession, grazing impact and herbivore selectivity of ciliate communities in response to winter warming.

This study aimed at simulating different degrees of winter warming and at assessing its potential effects on ciliate succession and grazing-related patterns. By using indoor mesocosms filled with unfiltered water from Kiel Bight, natural light and four different temperature regimes, phytoplankton spring blooms were induced and the thermal responses of ciliates were quantified. Two distinct ciliate assemblages, a pre-spring and a spring bloom assemblage, could be detected, while their formation was strongly temperature-dependent. Both assemblages were dominated by Strobilidiids; the pre-spring bloom phase was dominated by the small Strobilidiids Lohmaniella oviformis, and the spring bloom was mainly dominated by large Strobilidiids of the genus Strobilidium. The numerical response of ciliates to increasing food concentrations showed a strong acceleration by temperature. Grazing rates of ciliates and copepods were low during the pre-spring bloom period and high during the bloom ranging from 0.06 (Delta0 degrees C) to 0.23 day(-1) (Delta4 degrees C) for ciliates and 0.09 (Delta0 degrees C) to 1.62 day(-1) (Delta4 degrees C) for copepods. During the spring bloom ciliates and copepods showed a strong dietary overlap characterized by a wide food spectrum consisting mainly of Chrysochromulina sp., diatom chains and large, single-celled diatoms.

Osseous integration of calcium phosphate in osteoporotic vertebral fractures after kyphoplasty: initial results from a clinical and experimental pilot study.

INTRODUCTION: This study evaluated the radiological changes at the bone-cement interface of calcium phosphate cement (CPC) and polymethylmethacrylate (PMMA) 12 months after kyphoplasty. In a pilot experiment, we additionally performed a histomorphometric analysis in osteopenic foxhounds to analyze the process of osseous integration of CPC and PMMA. METHODS: Twenty postmenopausal female patients with 46 vertebral compression fractures (VCF) were treated by kyphoplasty, utilizing CPC (N=28) or PMMA (N=18) for intravertebral stabilization. After a 12-month follow-up, we measured the density changes of border voxels at the bone-cement interface by computed tomography (CT) using dedicated software algorithms. We defined the border-voxel density (BVD) as a parameter of cement resorption at the interface. We also investigated the bone-implant interface in three osteopenic foxhounds by histomorphometry 3, 6, and 12 months after cement implantation. RESULTS: Twelve months after kyphoplasty, only CPC showed a significant decrease of the BVD compared to PMMA (p<0.01), indicating a slow progress of resorption at the interface. Histomorphometry of the dog vertebrae showed near total bone coverage of CPC implants, whereas the PMMA surface exhibited only 30% direct bone contact (p<0.01). We also observed a time-dependent increase in the number of discernable osteons close to the interface of CPC, but no bone tissue within PMMA (p<0.01). CONCLUSIONS: The decrease of the BVD 12 months after kyphoplasty may indicate osseous integration of CPC by: (1) the ingrowth of bone tissue and (2) osteonal penetration close to the interface.

Endothelin-1 levels in patients with Paget's disease of bone.

A locally accelerated bone turnover is the pathophysiological basis of Paget's disease of bone (PD) and may result in severe bone deformations and pain. Affected bone sites are hypervascularized. Secreted endothelial products such as endothelin-1 (ET-1), influence bone metabolism. We investigated a possible correlation between ET-1 plasma concentrations and bone metabolism in patients with PD and whether ET-1 plasma levels are regulated by i. v. bisphosphonate treatment. Plasma ET-1 levels were determined in 22 patients with PD and found to be significantly (p = 0.006) elevated (0.75 +/- 0.48 fmol/ml) compared to 19 healthy controls (0.20 +/- 0.24 fmol/ml). In a group of five patients with PD, plasma ET-1 levels were determined before and after treatment with i. v. pamidronate. On the average, ET-1 levels decreased by 21 % after pamidronate infusions (p = 0.045). The results suggest that bone metabolism in pagetic bone affects endothelial cell metabolism and may also be modulated by endothelial cell products. ET-1 plasma levels may indicate PD activity.

[Use of mitomycin C (MMC) for dacryocystorhinostomy interventions]. / Utilisation de la mitomycine C pour les interventions de la dacryocystorhinostomie.

Mitomycin C (MMC) has been described as having a positive effect in different types of dacryocystorhinostomy (DCR) surgery such as external DCR, endonasal and transcanalicular DCR. MMC, an antineoplastic antibiotic, acts as an alkylating agent by inhibiting DNA, RNA and protein synthesis. Topical use of MMC can modulate the scarring process, which is useful in glaucoma surgery and pterygium excision. In DCR, MMC is also useful because it reduces the scarring process and thus prevents the occlusion of the osteotomy site related to the fibroblast activity. An increase in the success rate for long-term results has been observed by different authors, resulting from a larger osteotomy size as well as a decrease in the density and cellularity of the mucosa. No complications have been seen with topical use of MMC.

Olfactory function in patients with idiopathic Parkinson's disease: effects of deep brain stimulation in the subthalamic nucleus.

Decrease of olfactory function in patients with Parkinson's disease (PD) is a well-investigated fact. The present study aimed to investigate olfaction in PD patients with a specific focus on the effects of deep brain stimulation in the subthalamic nucleus. Eleven patients (age 42-67 years) participated in this study. Using the "Sniffin' Sticks", olfactory function was assessed based on butanol odor thresholds and the patients' ability to discriminate odors. Measures were taken with the stimulator being switched ON and OFF, respectively. While deep brain stimulation had no effect on odor thresholds, in hyposmic PD patients odor discrimination was found to be significantly higher during the ON period. This may indicate that deep brain stimulation has a positive effect on the cognitive processing of olfactory information in PD patients.

Fluid shear of low magnitude increases growth and expression of TGFbeta1 and adhesion molecules in human bone cells in vitro.

Deformation of the bone matrix by mechanical strain causes fluid shifts within the osteocytic canaliculi which affect osteocytic cell metabolism. We applied low fluid shear (1 - 63 micro Pa for 10 - 48 h) to human osteoblastic cells (HOB) in vitro to study its impact on cell proliferation and differentiated functions. Proteins involved in translating the physical force into a cellular response were characterised. Low fluid shear stress stimulated proliferation of HOB 1.2-fold when stress was applied intermittently for 24 h. Shear stress also increased differentiated cellular properties such as alkaline phosphatase (ALP) activity (121 % of control), fibronectin (FN) and fibronectin receptor (FNR) expression (290 % and 200 %, respectively). Prostaglandin E (2) (PGE (2)) and TGFbeta1 release into the medium were significantly stimulated when shear stress was applied for 6 - 12 h and 24 - 48 h, respectively. TGFbeta1 + 2 neutralising antibodies or the presence of indomethacine inhibited the mitogenic effect of fluid shear and reduced ALP activity to its control level. Furthermore, TGFbeta treatment induced a dose-dependent increase in FN and FNR expression. Therefore, fluid shear stress of low magnitude (a) suffices to affect HOB metabolism and (b) regulates anchorage of HOB via FN and FNR by stimulating osteoblastic PGE (2) and TGFbeta secretion.

Tritrichomonas foetus induces apoptotic cell death in bovine vaginal epithelial cells.

Tritrichomonas foetus is a serious veterinary pathogen, causing bovine trichomoniasis, a sexually transmitted disease leading to infertility and abortion. T. foetus infects the mucosal surfaces of the reproductive tract. Infection with T. foetus leads to apoptotic cell death of bovine vaginal epithelial cells (BVECs) in culture. An affinity-purified cysteine protease (CP) fraction yielding on sodium dodecyl sulfate-polyacrylamide gel electrophoresis a single band with an apparent molecular mass of 30 kDa (CP30) also induces BVEC apoptosis. Treatment of CP30 with the protease inhibitors TLCK (Nalpha-p-tosyl-l-lysine chloromethyl ketone) and E-64 [l-trans-epoxysuccinyl-leucylamide-(4-guanido)-butane] greatly reduces induction of BVEC apoptosis. Matrix-assisted laser desorption ionization-time-of-flight MALDI-TOF mass spectrometry analysis of CP30 reveals a single peak with a molecular mass of 23.7 kDa. Mass spectral peptide sequence analysis of proteolytically digested CP30 reveals homologies to a previously reported cDNA clone, CP8 (D. J. Mallinson, J. Livingstone, K. M. Appleton, S. J. Lees, G. H. Coombs, and M. J. North, Microbiology 141:3077-3085, 1995). Induction of apoptosis is highly species specific, since the related human parasite Trichomonas vaginalis and associated purified CPs did not induce BVEC death. Fluorescence microscopy along with the Cell Death Detection ELISA(PLUS) assay and flow cytometry analyses were used to detect apoptotic nuclear condensation, DNA fragmentation, and changes in plasma membrane asymmetry in host cells undergoing apoptosis in response to T. foetus infection or incubation with CP30. Additionally, the activation of caspase-3 and inhibition of cell death by caspase inhibitors indicates that caspases are involved in BVEC apoptosis. These results imply that apoptosis is involved in the pathogenesis of T. foetus infection in vivo, which may have important implications for therapeutic interference with host cell death that could alter the course of the pathology in vivo.

Discrimination of patients with and without vertebral fractures as measured by ultrasound and DXA osteodensitometry.

This study compares dual X-ray absorptiometry (DXA) measurements of the hip and spine with quantitative ultrasound (QUS) parameters measured simultaneously at the calcaneal and phalangeal bone in 174 patients with and without vertebral fractures. The aim of this study was to compare the ability of DXA and QUS measurements to discriminate patients with and without osteoporotic vertebral fractures and to evaluate whether QUS measurements in addition to the DXA measurements improve the clinical discrimination between patients with and without osteoporotic vertebral fractures. T-scores determined by DXA measurements at the spine and hip and QUS measurements at the calcaneus provide similar information regarding the discrimination of women with and without vertebral fractures. Phalangeal QUS measurements did not discriminate between patients with and without vertebral fractures. The discriminative power of the combined use of DXA and calcaneal QUS measurements to discern between patients with and without vertebral fractures increases in women. In contrast, the combined use of DXA and phalangeal QUS measurements resulted in decreased discriminative power as compared to DXA measurements alone. The number of fractures was higher in the quartiles with lower T-scores of the DXA and calcaneal QUS measurements whereas no difference was seen in the T-score quartiles of the phalangeal QUS device. These findings suggest that DXA and QUS measurements at weight-bearing skeletal sites provide useful information for assessing women with an anamnestic risk of osteoporotic bone loss. For DXA and calcaneal QUS measurements in men as well as for phalangeal QUS, however, a clinical algorithm remains to be established to understand the diagnostic implications and related therapeutic consequences of the obtained measurements.