Computer-assisted laser photocoagulation of the retina--a hybrid tracking approach

A system for robotically assisted retinal surgery has been developed to rapidly and safely place lesions on the retina for photocoagulation therapy. This system provides real-time, motion stabilized lesion placement for typical irradiation times of 100 ms. The system consists of three main subsystems: a digital-based global tracking subsystem; a fast, analog local tracking subsystem; and a confocal reflectance subsystem to control lesion parameters dynamically. We have reported previously on these individual subsystems. This paper concentrates on the development of a second hybrid system prototype. Considerable progress has been made toward reducing the footprint of the optical system, simplifying the user interface, fully characterizing the analog tracking system, using measurable lesion reflectance parameters to develop a noninvasive method to infer lesion depth, and integrating the subsystems into a seamless hybrid system. These system improvements and progress toward a clinically significant system are covered in detail within this paper. The tracking algorithms and concepts developed for this project have considerable potential for application in many other areas of biomedical engineering.     

Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype

OBJECTIVES: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes. METHODS: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry. RESULTS: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01). CONCLUSIONS: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.     

High density lipoprotein (HDL) reduces renal ischemia/reperfusion injury

High-density lipoproteins (HDL) have been shown to reduce organ injury and mortality in animal models of shock via modulation of the expression of adhesion molecules and pro-inflammatory enzymes. As renal inflammation plays an important role in the development of ischemia/reperfusion (I/R) injury of the kidney, the aim of this study was to investigate the ability of HDL to alleviate renal dysfunction and injury in a rat model of renal I/R. HDL (80 mg/kg, intravenous) was administered to male Wistar rats 30 min before bilateral renal ischemia for 45 min followed by reperfusion for up to 48 h. After 6-h reperfusion, HDL significantly reduced (1) renal and tubular dysfunction, (2) tubular and reperfusion-injury, and (3) histologic evidence of renal injury. HDL also improved renal function (after 24-h and 48-h reperfusion) and reduced histologic signs of renal injury (after 48-h reperfusion). Administration of HDL significantly reduced the numbers of polymorphonuclear leukocytes (PMN) infiltrating into renal tissues during reperfusion, which was reflected by an attenuation of the increase in renal myeloperoxidase activity caused by I/R. Furthermore, HDL markedly reduced expression of the adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), and P-selectin during reperfusion. The increase in renal malondialdehyde levels caused by renal I/R was also significantly reduced by HDL, suggesting attenuation of lipid peroxidation subsequent to oxidative stress. These results demonstrate that HDL significantly reduces renal I/R injury and severity of ischemic acute renal failure. It is proposed that the mechanism of protection involves reduction of the expression of adhesion molecules, resulting in reduction of PMN infiltration and oxidative stress.     

Sense of coherence predicts change in life satisfaction among home-living residents in the community with mental health problems: a 1-year follow-up study

Objectives There is a call for a further investigation of Sense of Coherence (SOC), the central concept in salutogenesis, and its relation to health and life satisfaction. No previous studies have investigated the utility of SOC versus mental symptoms for the prediction of life satisfaction among people with chronic mental health problems (MHP). Methods The present study has a prospective design including a baseline assessment and a 1-year follow up. We recruited 107 adults from the community health care system. SOC was measured by the Sense of Coherence questionnaire, mental symptoms by the Symptom Checklist-90 revised and life satisfaction by The Quality of Life Scale (all Norwegian versions). Results The results show that while SOC predicts change in life satisfaction (standardized beta coefficient for SOC was 0.39, P = 0.014), mental symptoms did not (standardized beta coefficient 0.00, P = 1.0). Conclusions These findings emphasize the importance of assessing factors that may explain differences in life satisfaction over and above mental symptoms among people with MHP. The results indicate that improving SOC among people with MHP might provide important opportunities for improving their life satisfaction.     

CYP2D6 is involved in O-demethylation of diltiazem

OBJECTIVE: In a previous study of diltiazem (DTZ) pharmacokinetics in renal transplant patients, we speculated that a polymorphic enzyme could be involved in O-demethylation of diltiazem. The aim of this in vitro study was to investigate whether O-demethylation of DTZ is mediated by cytochrome P450-2D6 (CYP2D6). METHODS: DTZ was incubated with transfected human liver epithelial (THLE) cells expressing CYP2D6 (T5-2D6 clone). Metabolism of DTZ was studied over a concentration range of 12.5-400 microM and in the presence of quinidine (a CYP2D6 inhibitor) or erythromycin (a CYP3A4 inhibitor). THLE cells lacking CYP2D6 activity (T5-neo clone) were used as control. The culture medium of the cells, in which DTZ was dissolved, was analysed for DTZ and metabolites prior to and after 8 h of incubation using high-performance liquid chromatography (HPLC, UV detection). Authentic O-demethyl-DTZ (Mx) was not available, and this metabolite was therefore not identifiable. RESULTS: Desacetyl-O-demethyl-DTZ (M4) was exclusively produced during incubations of DTZ with THLE cells expressing CYP2D6. The rate of M4 formation was described using Michaelis Menten kinetics in the concentration range of DTZ used. Production of M4 was inhibited by quinidine, but not erythromycin. An unidentified chromatographic peak, which was interpreted to be Mx, showed the same pattern of formation as M4 both in absence and presence of inhibitors. N-demethylated metabolites, formed by CYP3A4, were not observed in any of the cell lines. CONCLUSION: Evidence was provided in vitro that O-demethylation of DTZ is mediated by the polymorphic isoenzyme CYP2D6. Involvement of CYP2D6 in the metabolism of DTZ may have clinical implications regarding pharmacokinetic variability and interactions.     

Identifying Multiplicative Interactions Between Temporal Scales of Human Movement Variability

Conventional scaling analyses of human movement variability such as detrended fluctuation analyses assume that the movement variable can be decomposed into scale-dependent variation. However, these conventional scaling analyses are insensitive to multiplicative interactions within the movement variable. Multiplicative interactions refer to couplings between the scale-dependent variations across multiple scales that generate intermittent changes in the human movement variable. The mathematical concept for intermittent variability generated by multiplicative interactions is called multifractal variability. Multifractal variability is numerically defined by a spectrum of scaling exponents (i.e., a multifractal spectrum) that can be an important feature of coordinated movements and, consequently, relevant when aiming to identify movement disorders. In the current study, a new method is introduced based on detrended fluctuation analysis that can identify the multifractal spectrum from the temporal variation of local scaling exponents. The influence of multiplicative interactions on the local scaling exponents is tested by a Monte Carlo surrogate test. The methods are validated on multiplicative cascading processes with known multiplicative interactions. The application of the new methods is subsequently illustrated on an example of centre of pressure variations during quiet and relaxed standing. The results show that multiplicative interactions are present during periods with large movements of the center of gravity, where the movements of the centre of gravity and centre of pressure couple into coordinative structures. Further application and interpretation of the developed method for the study of human movement variability are discussed.     

Entering a World with No Future: A phenomenological study describing the embodied experience of time when living with severe incurable disease

Scand J Caring Sci; 2013; 27; 165–174 A phenomenological study describing the embodied experience of time when living with severe incurable disease This article presents findings from a phenomenological study exploring experience of time by patients living close to death. The empirical data consist of 26 open‐ended interviews from 23 patients living with severe incurable disease receiving palliative care in Norway. Three aspects of experience of time were revealed as prominent: (i) Entering a world with no future; living close to death alters perception of and relationship to time. (ii) Listening to the rhythm of my body, not looking at the clock; embodied with severe illness, it is the body not the clock that structures and controls the activities of the day. (iii). Receiving time, taking time; being offered – not asked for – help is like receiving time that confirms humanity, in contrast to having to ask for help which is like taking others time and thereby revealing own helplessness. Experience of time close to death is discussed as an embodied experience of inner, contextual, relational dimensions in harmony and disharmony with the rhythm of nature, environment and others. Rhythms in harmony provide relief, while rhythms in disharmony confer weakness and limit time.     

Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci

Background  

Estimates suggest that up to 30% of colorectal cancers (CRC) may develop due to an increased genetic risk. The mean age at diagnosis for CRC is about 70 years. Time of disease onset 20 years younger than the mean age is assumed to be indicative of genetic susceptibility. We have compared high resolution tumor genome copy number variation (CNV) (Roche NimbleGen, 385 000 oligo CGH array) in microsatellite stable (MSS) tumors from two age groups, including 23 young at onset patients without known hereditary syndromes and with a median age of 44 years (range: 28-53) and 17 elderly patients with median age 79 years (range: 69-87). Our aim was to identify differences in the tumor genomes between these groups and pinpoint potential susceptibility loci. Integration analysis of CNV and genome wide mRNA expression data, available for the same tumors, was performed to identify a restricted candidate gene list.     

Individual predictability of repeated spinal anaesthesia with plain 0.5% bupivacaine

To evaluate the individual predictability of spinal anaesthesia, 10 patients (3 women and 7 men) scheduled for control cystoscopy were studied twice within 9 months. Lumbar puncture was performed in the midline at the L2/3 interspace with the patient in the sitting position using plain 0.5% bupivacaine at 37 degrees C. A non-parametric Spearman test showed that, on the basis of the first block, the predictability of the cephalad analgesic spread of the second anaesthesia was high up to 60 min after injection. Thereafter the predictability decreased. The predictability of the motor blockade was generally low. Six patients obtained complete motor blockade twice; the remaining four, once.