Non-Compliance after a Kidney-Pancreas Transplantation -A Narrative Case-Analysis Involving Different Patient-Physician Relationships and Ethical Frames

Background: Non-compliance is one of the most frustrating causes of long-term allograft failure. Despite the frequency of this phenomenon, the clinical-psychological approach has not yet been standardised. Aim: To describe the use of a narrative approach based upon the identification of the best patient-physician interaction model and of the best ethical framework, in the clinical management of a noncompliant pancreas-kidney graft patient. Methods and results: The case: a 30 year-old woman, diabetic since adolescence, recipient of a preemptive kidney-pancreas transplant. No psychological or behavioural problem had been observed or reported before transplantation. After the graft, a benzodiazepine addiction was diagnosed (withdrawal syndrome). She experienced two rejection episodes (low Cyclosporine levels), and discontinued steroids (Cushingoid appearance). She repeatedly refused psychological help and wanted to be managed by her physicians only. The three tested models were: parental-paternalistic (the "static model" according to Hippocrates and the "dynamic model" according to Moses Maimonides); self-determination of the patient; and therapeutic alliance. The four classic principles of the ethical approach (beneficium, non maleficium, autonomy and justice) and the narrative approach were also applied. Due to her psychological fragility, a paternalistic approach was chosen as the basis for the relationship. Furthermore, due to the problems in defining her "autonomy", and considering her benzodiazepine abuse, an integrated, dynamic, narrative, ethical approach was chosen. Pragmatic solutions required frequent clinical controls, as a means to supervise compliance. Despite occasional wide swings in her Cyclosporine A levels, she is presently well compensated, working full-time and free from further major non-compliance or drugabuse episodes. Conclusion: While this case raises several unanswered questions such as the practical classification of autonomy, competence and compliance, the definition of the setting of the patient-physician relationship and the systematic discussion of different ethical approaches may help the clinician to tailor interventions and to find adequate, tailored solutions

Genetics of migraine in the age of genome-wide association studies

Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine

The primary headaches: genetics, epigenetics and a behavioural genetic model

The primary headaches, migraine with (MA) and without aura (MO) and cluster headache, all carry a substantial genetic liability. Familial hemiplegic migraine (FHM), an autosomal dominant mendelian disorder classified as a subtype of MA, is due to mutations in genes encoding neural channel subunits. MA/MO are considered multifactorial genetic disorders, and FHM has been proposed as a model for migraine aetiology. However, a review of the genetic studies suggests that the FHM genes are not involved in the typical migraines and that FHM should be considered as a syndromic migraine rather than a subtype of MA. Adopting the concept of syndromic migraine could be useful in understanding migraine pathogenesis. We hypothesise that epigenetic mechanisms play an important role in headache pathogenesis. A behavioural model is proposed, whereby the primary headaches are construed as behaviours, not symptoms, evolutionarily conserved for their adaptive value and engendered out of a genetic repertoire by a network of pattern generators present in the brain and signalling homeostatic imbalance. This behavioural model could be incorporated into migraine genetic research

End-stage renal failure due to amyloidosis and recurrent fever on dialysis--is there a link?

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Active SLAM using Connectivity Graphs as Priors

Mobile robots can be considered completely autonomous if they embed active algorithms for Simultaneous Localization And Mapping (SLAM). This means that the robot is able to autonomously, or actively, explore and create a reliable map of the environment, while simultaneously estimating its pose. In this paper, we propose a novel framework to robustly solve the active SLAM problem, in scenarios in which some prior information about the environment is available in the form of a topo-metric graph. This information is typically available or can be easily developed in industrial environments, but it is usually affected by uncertainties. In particular, the distinguishing features of our approach are: the inclusion of prior information for solving the active SLAM problem; the exploitation of this information to pursue active loop closure; the on-line correction of the inconsistencies in the provided data. We present some experiments, that are performed in different simulated environments: the results suggest that our method improves on state-of-the-art approaches, as it is able to deal with a wide variety of possibly large uncertainties

OXIDATIVE STRESS MODULATION OF DCT1

Iron plays a key role in a number of metabolic functions. Its deficiency as well as its overload leads to important pathologies in humans. The functional properties and the localization of the divalent cation transporter (DCT1/Nramp2/DMT1) indicate its weight in the direct cellular iron uptake and in the transferrin-receptor mediated pathway (H.Gunshin et al. Nature 388: 482-488, 1997). To study the influence of redox reagents on DCT1 function we used the Xenopus l. oocyte expression system and analyzed the transport activity with iron and zinc uptake assays, and electrophysiology experiments. Our radiotracer experiments confirmed the capability of DCT1 to mediate Zn uptake suggested on the basis of electrophysiology experiments. Therefore we used Zn2+, which does not react with redox reagents used in our study. Hydrogen peroxide treatment resulted in an inhibition of about 40% of zinc induced DCT1 mediated current in oocytes. DCT1 sequence contains several amino acid residues that could be targets for oxidant reagents. Hg2+ administration exerted the same inhibition than H2O2 and, in both cases, DCT1 function was fully recovered after perfusion with dithiotreitol, strongly indicating the involvement of cysteine residues. Mutagenesis experiments allowed us to identify a cysteine involved in the mechanism of DCT1 inhibition. C248 is thought to be located in the third-outer loop of the predicted secondary structure of the transporter and could represent a sensor that allows the cell to prevent iron overload in oxidative-stress conditions. The finding of a direct inhibition of iron transport appears to have relevant physiological interest to understand the regulation of iron metabolism and the defensive mechanisms to preserve cell from oxidative injur