A new process-centered description tool to initiate meta-reporting methodology in healthcare - 7CARECAT™. Feasibility study in a post-anesthesia care unit.

BACKGROUND: In the healthcare domain, different analytic tools focused on accidents appeared to be poorly adapted to sub-accidental issues. Improving local management and intra-institutional communication with simpler methods, allowing rapid and uncomplicated meta-reporting, could be an attractive alternative. METHODS: A process-centered structure derived from the industrial domain - DEPOSE(E) - was selected and modified for its use in the healthcare domain. The seven exclusive meta-categories defined - Patient, Equipment, Process, Actor, Supplies, work Room and Organization- constitute 7CARECAT™. A collection of 536 "improvement" reports from a tertiary hospital Post anesthesia care unit (PACU) was used and four meta-categorization rules edited prior to the analysis. Both the relevance of the metacategories and of the rules were tested to build a meta-reporting methodology. The distribution of these categories was analyzed with a χ 2 test. RESULTS: Five hundred and ninety independent facts were collected out of the 536 reports. The frequencies of the categories are: Organization 44%, Actor 37%, Patient 11%, Process 3%, work Room 3%, Equipment 1% and Supplies 1%, with a p-value <0.005 (χ 2). During the analysis, three more rules were edited. The reproducibility, tested randomly on 200 reports, showed a <2% error rate. CONCLUSION: This meta-reporting methodology, developed with the 7CARECAT™ structure and using a reduced number of operational rules, has successfully produced a stable and consistent classification of sub-accidental events voluntarily reported. This model represents a relevant tool to exchange meta-informations important for local and transversal communication in healthcare institutions. It could be used as a promising tool to improve quality and risk management.

Development of a 25-plex SNP assay for traceability in cattle.

Single nucleotide polymorphisms (SNPs) are amenable to automation and therefore have become the marker of choice for DNA profiling. SNaPshot, a primer extension-based method, was used to multiplex 25 SNPs that have been previously validated as useful for identity control. Detection of extended products was based on four different fluorochromes and extension primers with oligonucleotide tails of differing lengths, thus controlling the concise length of the entire chromatogram to 81 bases. Allele frequencies for Holstein, Simmental, Limousin, Angus, Charolais and Tux Cattle were estimated and significant positive Pearson-correlation coefficients were obtained among the analysed breeds. The probability that two randomly unrelated individuals would share identical genotypes for all 25 loci varied from 10(-8) to 10(-10) for these breeds. For parentage control, the exclusion power was found to be 99.9% when the genotypes of both putative parents are known. A traceability test of duplicated samples indicated a high genotyping precision of >0.998. This was further corroborated by analysis of 60 cases of parent-sib pairs and trio families. The 25-plex SNaPshot assay is adapted for low- and high-throughput capacity and thus presents an alternative for DNA-based traceability in the major commercial cattle breeds.

[Neurobiology of the chronicisation of pain in children: the memory of pain and its painful memory]. / La neurobiologie de la chronicisation de la douleur chez l'enfant: la mémoire de la douleur et la douleur de la mémoire.

Reviewing the development of nociceptive circuits provides the rationale behind the need to modify and reduce premature painful experiences, especially during the "plastic" neonatal phase. Indeed, if physiological mechanisms of the functional nociceptive system follow a harmonious and predetermined development, it is the individual personal experience, intrinsically random, which will shape the final reactivity of this system and the later painful experience. If pain would not have been the organism's alarm system, we could have simply compared it by analogy to other sensorial systems, which its development depends exclusively on the presence of environmental stimuli. The eyes wait for light, the ears for sound, the skin to be touched, the tongue to taste and the olfactory bulbs to smell. However with pain it is not the quantitative exposure that determines its development, but rather the context-laden aspects of its affliction which in turn create the complex experience and "memory" of pain. Prolonged, but also "unnecessary" exposure to pain transforms it into a futile sensation, which impacts the individual immediately but also resonates into its future. This article reviews recent neurobiological mechanisms (such as neural circuitry, neurotrophins, peripheral and central sensitization, inhibitory pathways) now known to develop during the chronicisation and apprenticing of pain in the growing individual. Its cognizance is vital for a better comprehension of adult pain.

[Novelties in interventional pain techniques]. / Actualités en antalgie interventionnelle.

The clinical application of new interventional technology begins with its conception, passes through a scientific validation and finally should be accepted as part of current clinical practice. One way of scientifically validating these techniques is analyzing present practice, available resources and patient outcome. The first part of this article describes the stages in the creation of a quality management system (ISO 9001) which we carried out, in order to judiciously realize these novel interventions. In the second part two techniques indicated in low back and leg pain are described. The first is spinal endoscopy, a three dimensional procedure designed to diagnose and treated painful lumbar radiculopathy. The second is intra-discal electro-therapy (IDET), indicated in discogenic pain. Albeit novel, these techniques are of promising nature, and their qualitative analysis, via rigorous certification is, we think, of interest.

[Mechanisms by which acute orofacial pain becomes chronic]. / Mécanismes de la chronicisation de la douleur oro-faciale aiguë.

Pain is a complex, multidimensional experience encompassing sensory-discriminative, cognitive, emotional and motivational dimensions. These dimensions in the orofacial region have particular expression since the face and mouth have special biological, emotional and psychological meaning to each individual. Orofacial pain is frequent. Epidemiological studies reveal a high prevalence of severe pain in syndromes such as temporomandibular disorders (TMD), burning mouth syndrome and toothaches, as well as an important role of psychosocial influences, contributing to the persistence of these syndromes. Many of the difficulties experienced by clinicians with the diagnosis and management of acute and chronic orofacial pain stem from a lack of recognition and understanding of these complex conditions, the various intricate bio-psycho-social interactions and the neurobiology behind the chronicisation of acute pain. This text strives to review the important advances and insights into the peripheral processes by which noxious stimuli activates or modulates nociceptive afferent input into the brainstem, the neural pathways in the brainstem and higher levels of the trigeminal (V) somatosensory system and the mechanisms involved in the plasticity of nociceptive transmission. We shall link this knowledge to clinical correlates and suggest a therapeutic approach in acute orofacial pain, in the attempt to avoid the development of chronic pain.

Minimally invasive procedures for the treatment of failed back surgery syndrome.

Failed back surgery syndrome has become unfortunately a common clinical entity. FBSS does not have one specific treatment because it does not have one specific cause. Some features are shared with chronic low back pain (CLBP) and some pathological processes are specific. Both pathologies are leading causes of disability in the industrialized world and costly medical and surgical treatments are continuously used despite their limited efficacy. Nonetheless, evidence based practice guidelines are systematically developed. In this chapter we cautiously review the vast, complex and at times contradictory literature regarding the treatment of FBSS. Interventional Pain literature suggests that there is moderate evidence (small randomized or non randomized or single group or matched case controlled studies) for medial branch neurotomy and limited evidence (non experimental one or more center studies) for intra-discal treatments in mechanical low back pain. There is moderate evidence for the use of transforaminal epidural steroid injections, lumbar percutaneous adhesiolysis and spinal endoscopy for painful lumbar radiculopathy and spinal cord stimulation and intrathecal pumps mostly after spinal surgery. In reality there is no gold standard for the treatment of FBSS but, these results seem promising.

Trophic signals acting via phosphatidylinositol-3 kinase are required for normal pre-implantation mouse embryo development.

The growth and survival of the preimplantation mammalian embryo may be regulated by several autocrine trophic factors that have redundant or overlapping actions. One of the earliest trophic factors to be produced is embryo-derived platelet-activating factor (1-O-alky-2-acetyl-sn-glyceryl-3-phosphocholine). The addition of platelet-activating factor to embryo culture media exerted a trophic effect, but structurally related lipids (3-O-alky-2-acetyl-sn-glyceryl-1-phosphocholine, 1-O-alky-sn-glyceryl-3-phosphocholine, octadecyl-phosphocholine) had no effect. Platelet-activating factor induced a pertussis toxin-sensitive [Ca(2+)](i) transient in two-cell embryos that did not occur in platelet-activating factor-receptor null (Pafr-/-) genotype embryos. Fewer Pafr-/- mouse zygotes developed to the blastocyst stage in vitro compared with Pafr+/+ zygotes (P<0.02), those that developed to blastocysts had fewer cells (P<0.001) and more cells with fragmented nuclei (P<0.001). The inhibition of 1-O-phosphatidylinositol 3-kinase (LY294002 (3 microM and 15 microM) and wortmannin (10 nM and 50 nM)) caused a dose-dependent inhibition of platelet-activating factor-induced [Ca(2+)](i) transients (P<0.001). The two-cell embryo expressed 1-O-phosphatidylinositol 3-kinase catalytic subunits p110 alpha, beta, gamma and delta, and regulatory subunits p85 alpha and beta. LY294002 and wortmannin each caused a significant reduction in the proportion of embryos developing to the morula and blastocyst stages in vitro, reduced the number of cells within each blastocyst, and significantly increased the proportion of cells in blastocysts with fragmented nuclei. The results indicate that embryo-derived platelet-activating factor (and other embryotrophic factors) act through its membrane receptor to enhance embryo survival through a 1-O-phosphatidylinositol 3-kinase-dependent survival pathway.

Subdural catheter migration may lead to baclofen pump dysfunction.

OBJECTIVES: To report an unusual cause of intrathecal drug delivery failure in baclofen pump device. STUDY DESIGN: A case report of an SCI patient treated with intrathecal baclofen, presenting a drug withdrawal. SETTING: Regional spinal cord injuries centre in Geneva (Switzerland). METHODS: We present a case of a 38-year-old male with complete T9 spastic paraplegia for 15 years, treated with intrathecal baclofen for 11 years. He recently presented to our centre with a spastic hypertonic episode, associated with rhabdomyolysis. RESULTS: Standard investigations were unrevealing. However, a CT scan performed after injecting a radio-opaque solution by the side port of the pump, showed an unexpected catheter migration into the subdural space. Surgical revision reversed withdrawal symptoms. CONCLUSIONS: Subdural catheter migration must be considered in the differential diagnosis of intrathecal drug delivery system failures. We recommend the use of the CT scan after contrast injection, to detect the localization of the distal catheter tip and confirm the normal diffusion into the subarachnoid space.

A study of the nature of embryonic lethality in LIS1-/- mice.

Homozygous deletion of the Lis1 gene (Lis1(-/-)) in mouse resulted in early embryonic lethality immediately after embryo implantation by an undefined mechanism. We seek to define the nature of this demise. LIS1 (pafah1b1) is a 46 kDa protein with seven tryptophan-aspartate (WD) repeats. It docks with many proteins and has been implicated in microtubular function, cell division, intercellular transport, and nuclear and cellular motility. Combined Western and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed that LIS1 expression from the blastocyst stage required new transcription from the embryonic genome. Consequently, the death of post-implantation embryos may not reflect the first time during development that LIS1 was required, rather, it may reflect the first time following depletion of gametic stores that its actions were essential. Following culture of blastocysts in vitro for 96 hr the inner cell mass (ICM) of null embryos were significantly smaller than ICM of wild-type siblings. Normal blastocyst outgrowths after 96-hr culture had high levels of LIS1 expression in the outer cells of developing ICM and extensive expression in trophoblast cells. Lis1(-/-) embryos had significantly smaller trophoblast nuclei than wild-type embryos. The results show that LIS1 expression is required for the continued normal development of the ICM and optimal trophoblast giant cell formation.

LIS1-no more no less.

LIS1 is one of the genes that has a principle role in brain development since hemizygote mutations in LIS1 result in a severe brain malformation known as lissencephaly ('smooth brain'). LIS1 is a WD repeat protein and is known to be involved in several protein complexes that are likely to play a functional role in brain development. We discuss here the brain developmental phenotype observed in mice heterozygote for an N-terminal truncated LIS1 protein in view of known LIS1 protein interactions.

Phenotype of the 22q11.2 deletion in individuals identified through an affected relative: cast a wide FISHing net!

PURPOSE: The chromosome 22q11.2 deletion has been identified in the majority of patients with DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome and in some patients with the autosomal dominant Opitz G/BBB syndrome and Cayler cardiofacial syndrome. In addition, 22q11.2 deletion studies are becoming part of a standardized diagnostic workup for some isolated defects such as conotruncal cardiac anomalies and velopharyngeal incompetence. However, there is little information available on the clinical findings of unselected patients. For example, those individuals identified during prenatal diagnosis, as part of a generalized screening protocol, or following the diagnosis in a relative. This information will be invaluable in defining the variability of the disorder and in observing long-term outcome in the absence of targeted remediations. This study allows one to examine the first unselected cohort of patients and serves to highlight the importance of deletion testing in parents of affected probands. METHODS: Thirty individuals with a 22q11.2 deletion were identified following the diagnosis in a relative. Nineteen were adults ascertained only following the diagnosis in their child, 10 were children identified following the diagnosis in their sibling, and one was a child diagnosed prenatally following the diagnosis in her parent. RESULTS: Sixty percent of patients had no visceral anomalies. In fact, only 6 of the 19 adults (32%) and 6 of the 11 children (55%) had major findings which would have brought them to medical attention. Deletion sizing demonstrated the same large 3-4 MB deletion in most families despite wide inter and intrafamilial variability and there was no difference in clinical findings based on the parent of origin. Thus, no genotype-phenotype correlations could be made. CONCLUSION: We report the first unselected cohort of patients with the 22q11.2 deletion identified through an affected relative. Analysis of this series of 30 patients, many with very mild manifestations of the deletion, allows one to examine the outcome in individuals who lacked specific remediations for this disorder. It emphasizes the importance of broadening the index of suspicion in order to provide appropriate recurrence risk counseling, cognitive remediation, and medical management. Further, it underscores the lack of familial concordance and the current lack of genotype-phenotype correlations in this disorder, and it raises the possibility that the deletion is more common than previously reported.

Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization.

Lissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimics a mutation described in one lissencephaly patient with a milder phenotype. Homozygotes are early lethal, although heterozygotes are viable and fertile. Most strikingly, the morphology of cortical neurons and radial glia is aberrant in the developing cortex, and the neurons migrate more slowly. This is the first demonstration, to our knowledge, of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalomocortical innervation are also abnormal. Biochemically, the mutant protein is not capable of dimerization, and enzymatic activity is elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of PAF-AH. This mutation allows us to determine a hierarchy of functions that are sensitive to LIS1 dosage, thus promoting our understanding of the role of LIS1 in the developing cortex.

Continuous psoas compartment block for anesthesia and perioperative analgesia in patients with hip fractures.

BACKGROUND AND OBJECTIVES: The perioperative use of continuous psoas compartment block (CPCB) was compared with traditional pain management for patients with fracture of the femur. The anatomy of CPCB was also tested in cadavers. METHODS: Forty consecutive patients (range, 67-96 years old) were prospectively randomized either to group A (given local anesthetics using a CPCB) or group B (given perioperative analgesia with meperidine). In another part of the study, CPCB was performed in 15 fresh cadavers, and dissection of the lumbar region was performed after dye injection. RESULTS: Continuous psoas compartment block was performed successfully in all patients in group A and was used in the pre- (16-48 hours) and postoperative (72 hours) periods. Visual analog scale score in group A was lower than in group B in 5/7 preoperative and 9/9 postoperative 8 hourly assessments. Differences reached statistical significance (P < .05) in 3 and 5 of the assessments, respectively. Patient satisfaction was higher in group A in the pre- (P < .05) and postoperative periods (P<.03). The block failed to achieve surgical anesthesia in 85% (17/20) of the patients, and additional anesthesia was needed. The anatomic study failed to support the existence of a defined "psoas compartment" previously described, and supported the clinical findings. Injected dye was found in the region of the origin of the sciatic nerve (essential for the production of anesthesia for hip surgery) in only 26% (4/15) of cadavers. CONCLUSIONS: The CPCB seems to be an appropriate technique for efficient and safe perioperative pain control. However, in our dissections, the psoas compartment was not well defined in all patients, thus, using this route for anesthesia may result in only partial success.

Analysis of lissencephaly-causing LIS1 mutations.

Mutations in the LIS1 gene may result in severe abnormalities of brain cortical layering known as lissencephaly. Most lissencephaly-causing LIS1 mutations are deletions that encompass the entire gene, therefore the mechanism of the disease is regarded as haploinsufficiency. So far, 13 different intragenic mutations have been reported: one point mutation, H149R; deletion of exon 9, which results in deleted acids Delta301-334; deletion of exon 4, which results in deleted amino acids Delta40-64; 10 mutations resulting in truncated proteins and one predicted to result in extra amino acids. We studied the consequences of the point mutation, deletion mutation and one of the reported truncations. In order to study LIS1 structure function, we introduced an additional point mutation and other truncations in different regions of the protein. The consequences of these mutations to protein folding were studied by gel filtration, sucrose density gradient centrifugation and measuring resistance to trypsin cleavage. On the basis of our results, we suggest that all truncation mutations and lissencephaly-causing point mutations or internal deletion result in a reduction in the amount of correctly folded LIS1 protein.

Cystic fibrosis mutations in Israeli Arab patients.

Mutation analysis was performed on 42 unrelated Israeli Arab CF patients. The previously known mutations in this population, DF508, N1303K, G542X, 4010delTATT, and S549R(T>G), were identified in 57 CF alleles, leaving 28 CF alleles with unknown mutations. Screening of the coding sequence of the CFTR gene by a single strand conformation analysis (SSCA) and direct sequencing revealed three point mutations and two intragenic deletions, including 2183AA>G, R75X, S549R (A>C), 3120+1Kbdel8.6Kb and del(exon2). In the present sample of Israeli Arab patients, 12 mutations account for 92% of the CF alleles. The mutations DF508, N1303K, W1282X and 3120+1Kbdel8.6Kb were found in all Arab ethnic subgroups. The mutations G85E, R75X, 2183AA>G, and del(exon2) were confined to Muslim Arabs, and the mutations 4010delTATT, S549R(A>C) and G542X were confined to Christian Arabs. Hum Mutat 14:543, 1999.

LIS1 is a microtubule-associated phosphoprotein.

Lissencephaly, a severe brain malformation, may be caused by mutations in the LIS1 gene. LIS1 encodes a microtubule-associated protein (MAP) that is also part of the enzyme complex, platelet-activating factor acetylhydrolase. LIS1 is also found in a complex with two protein kinases; a T-cell Tat-associated kinase, which contains casein-dependent kinase (CDK) activating kinase (CAK), as well as CAK-inducing activity, and with a spleen protein-tyrosine kinase similar to the catalytic domain of p72syk. As phosphorylation is one of the ways to control cellular localization and protein-protein interactions, we investigated whether LIS1 undergoes this post-translational modification. Our results demonstrate that LIS1 is a developmentally regulated phosphoprotein. Phosphorylated LIS1 is mainly found in the MAP fraction. Phosphoamino acid analysis revealed that LIS1 is phosphorylated on serine residues. Alkaline phosphatase treatment reduced the number of visible LIS1 isoforms. In-gel assays demonstrate a 50-kDa LIS1 kinase that is enriched in microtubule-associated fractions. In vitro, LIS1 was phosphorylated by protein kinase CKII (casein kinase II), but not many other kinases that were tested. We suggest that LIS1 activity may be regulated by phosphorylation.

A comparison of the placental transfer of ropivacaine versus bupivacaine.

UNLABELLED: This study compares the placental transfer of ropivacaine and bupivacaine using the dual perfused, single cotyledon human placental model. We studied the effects of maternal/fetal protein binding, maternal ropivacaine concentration, and fetal pH on ropivacaine transfer. At a clinically relevant maternal concentration (1 microg/mL), the calculated transfer ratios (local anesthetic percent transfer/antipyrine percent transfer) of ropivacaine (0.82 +/- 0.03) and bupivacaine (0.74 +/- 0.01) were comparable at the completion of the perfusion experiment (120 min). When the perfusates were modified to simulate actual in vivo plasma protein binding values, the maternal-to-fetal transfer of ropivacaine and bupivacaine decreased significantly (P < 0.05) as indicated by transfer ratios of 0.42% +/- 0.07% and 0.40% +/- 0.03%, respectively. No saturation of the transfer process was observed for either drug at the maternal concentrations investigated. The placental transfer of both local anesthetic agents increased significantly as the fetal pH decreased. This investigation shows that ropivacaine and bupivacaine cross the human placenta at a similar rate, despite their differences in lipophilicity and stereochemistry. Placental transfer of both compounds is highly influenced by maternal and fetal protein concentration and the fetal pH. IMPLICATIONS: The placental transfer of ropivacaine was shown to be similar to that of bupivacaine, and is thus highly influenced by the degree of maternal and fetal protein binding and fetal pH.

Platelet-activating factor (PAF) acetylhydrolase activity, LIS1 expression, and seizures.

Lissencephaly patients are born with severe brain malformations and suffer from recurrent seizures. LIS1, the gene mutated in isolated lissencephaly patients, is a subunit of the heterotrimeric cytosolic enzyme platelet-activating factor acetylhydrolase (PAF-AH), interacts with tubulin, and affects microtubule dynamics. In order to gain molecular insights into the possible involvement of LIS1 in seizures in lissencephaly patients, we induced seizures in rats by injection of kainate. PAF-AH activity was markedly reduced as early as 30 min following initiation of seizures, making this parameter a sensitive indicator of seizure events. PAF-AH activity returned to and surpassed control values 1 week following initiation of seizures. Expression of LIS1 in the dentate gyrus changed significantly in a manner similar to that of PAF-AH enzymatic activity. This is the first correlation found between LIS1 expression and PAF-AH activity. Furthermore, the expression of the alpha2 catalytic subunit, which is the major PAF-AH catalytic subunit in rat adult brain, changed in a dramatic fashion. An additional higher-mobility LIS1 cross-reactive band was detected in samples isolated a week following seizure occurrence. This LIS1 isoform was enriched in the microtubule-associated fraction. We propose that LIS1 expression is an important factor in regulation of PAF-AH activity. We postulate that reductions in LIS1 protein levels found in lissencephaly patients may render them more susceptible to seizures.