Markers of Endothelial-to-Mesenchymal Transition: Evidence for Antibody-Endothelium Interaction during Antibody-Mediated Rejection in Kidney Recipients.

Antibody-mediated rejection (ABMR) is a leading cause of allograft loss. Treatment efficacy depends on accurate diagnosis at an early stage. However, sensitive and reliable markers of antibody-endothelium interaction during ABMR are not available for routine use. Using immunohistochemistry, we retrospectively studied the diagnostic value of three markers of endothelial-to-mesenchymal transition (EndMT), fascin1, vimentin, and heat shock protein 47, for ABMR in 53 renal transplant biopsy specimens, including 20 ABMR specimens, 24 cell-mediated rejection specimens, and nine normal grafts. We validated our results in an independent set of 74 unselected biopsy specimens. Endothelial cells of the peritubular capillaries in grafts with ABMR expressed fascin1, vimentin, and heat shock protein 47 strongly, whereas those from normal renal grafts did not. The level of EndMT marker expression was significantly associated with current ABMR criteria, including capillaritis, glomerulitis, peritubular capillary C4d deposition, and donor-specific antibodies. These markers allowed us to identify C4d-negative ABMR and to predict late occurrence of disease. EndMT markers were more specific than capillaritis for the diagnosis and prognosis of ABMR and predicted late (up to 4 years after biopsy) renal graft dysfunction and proteinuria. In the independent set of 74 renal graft biopsy specimens, the EndMT markers for the diagnosis of ABMR had a sensitivity of 100% and a specificity of 85%. Fascin1 expression in peritubular capillaries was also induced in a rat model of ABMR. In conclusion, EndMT markers are a sensitive and reliable diagnostic tool for detecting endothelial activation during ABMR and predicting late loss of allograft function.

Toward unsupervised outbreak detection through visual perception of new patterns.

BACKGROUND: Statistical algorithms are routinely used to detect outbreaks of well-defined syndromes, such as influenza-like illness. These methods cannot be applied to the detection of emerging diseases for which no preexisting information is available.This paper presents a method aimed at facilitating the detection of outbreaks, when there is no a priori knowledge of the clinical presentation of cases. METHODS: The method uses a visual representation of the symptoms and diseases coded during a patient consultation according to the International Classification of Primary Care 2nd version (ICPC-2). The surveillance data are transformed into color-coded cells, ranging from white to red, reflecting the increasing frequency of observed signs. They are placed in a graphic reference frame mimicking body anatomy. Simple visual observation of color-change patterns over time, concerning a single code or a combination of codes, enables detection in the setting of interest. RESULTS: The method is demonstrated through retrospective analyses of two data sets: description of the patients referred to the hospital by their general practitioners (GPs) participating in the French Sentinel Network and description of patients directly consulting at a hospital emergency department (HED).Informative image color-change alert patterns emerged in both cases: the health consequences of the August 2003 heat wave were visualized with GPs' data (but passed unnoticed with conventional surveillance systems), and the flu epidemics, which are routinely detected by standard statistical techniques, were recognized visually with HED data. CONCLUSION: Using human visual pattern-recognition capacities to detect the onset of unexpected health events implies a convenient image representation of epidemiological surveillance and well-trained "epidemiology watchers". Once these two conditions are met, one could imagine that the epidemiology watchers could signal epidemiological alerts, based on "image walls" presenting the local, regional and/or national surveillance patterns, with specialized field epidemiologists assigned to validate the signals detected.

OPTISAS a new method to analyse patients with Sleep Apnea Syndrome.

OPTISAS is a visualization method that allows describing very precisely a patient with Sleep Apnea Syndrome. Using the events scored by the physician, our method gives a set of graphs that are a detailed representation of the condition, sleep stage and position, in which the events occur. This helps for the diagnosis. This is possible thanks to the application of Generalized Caseview method. The method proceeds in two steps, defining the reference frame and using this reference frame to visualize data. The reference frame is built by using a supin/unsupine binary criterion, a six type event criterion and a sleep stage ordinal criterion. The main result is the visualization of the indexes (average number of events by hour) associated with the events. This allows a more accurate diagnosis showing the precise influence of the position and of the sleep stage on the events.

4h versus 1h-nap-video-EEG monitoring in an Epileptology Unit.

OBJECTIVE: To compare the performance of 4h-video EEG monitoring (VEEG) and 1h-nap-VEEG in an Epileptology Unit. METHODS: We examined short-term VEEG data from 196 patients admitted to characterize their: (i) clinical events; (ii) epileptic syndromes or (iii) state after status epilepticus or surgery. We compared the 4h-VEEG and 1h-nap-VEEG performances using three measures: (i) the capability to detect epileptic seizures (ES), psychogenic non-epileptic seizures (PNES), interictal epileptiform abnormalities (IEA) and sleep-related IEA; (ii) the usefulness to answer questions on referral; (iii) the sensitivity for the final diagnosis. RESULTS: The 4h-VEEG test recorded clinical events in 53.6% of 196 patients, IEA in 41.3%, sleep-related IEA in 34.7%, and was judged as useful in 66.8%. The 4h-VEEG was compared to the 1h-nap-VEEG in 129 patients. 4h-VEEG had a better capability to record clinical events (50.3% vs. 6.2%, p<0.001), a higher usefulness (63.5% vs. 37.2%, p<0.001), and a higher sensitivity for both ES (69.3% vs. 49.3%, p=0.0035) and PNES (61.3% vs. 15.4%, p=0.0014) than nap-EEG. CONCLUSIONS: This work found 4h-VEEG records were superior to the 1h-nap-VEEG test on the basis of three complementary measures, capability, usefulness and sensitivity. SIGNIFICANCE: 4h-VEEG is a useful alternative investigation tool in an Epileptology Unit.

Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations.

TP53 alteration is the most frequent genetic alteration found in human cancers. To date, more than 15,000 tumors with TP53 mutations have been published, leading to the description of more than 1,500 different TP53 mutants (http://p53.curie.fr). The frequency of these mutants is highly heterogeneous, with 11 hotspot mutants found more than 100 times, whereas 306 mutants have been reported only once. So far, little is known concerning the biological significance of these rare mutants, as the majority of biological studies have focused on classic hotspot mutants. In order to gain a deeper knowledge about the significance of all of these mutants, we have cross-checked each mutant of the TP53 mutation database for its activity, derived from a library of 2,314 TP53 mutants representing all possible amino acid substitutions caused by a point mutation. The transactivation activity of all of these mutant was analyzed with respect to eight transcription promoters [Kato S, et al., Proc Natl Acad Sci USA (2003)100:8424-8429]. Although the most frequent TP53 mutants sustain a clear loss of transactivation activity, more than 50% of the rare TP53 mutants display significant activity. Analysis in specific types of cancer or in normal skin patches demonstrates a similar distribution of TP53 loss of activity, with the exception of melanoma, in which the majority of TP53 mutants display significant activity. Our data indicate that TP53 mutants represent a highly heterogeneous population with a large diversity in terms of loss of transactivation activity that could account for the heterogeneous tumor phenotypes and the difficulty of clinical studies.

Underperception of Naps in Older Adults Referred for a Sleep Assessment: An Insomnia Trait and a Cognitive Problem?

OBJECTIVES: To examine the frequency and determinants of underperception of naps in older adults referred for a sleep assessment. DESIGN: Prospective study. SETTING: Outpatient geriatric sleep clinic. PARTICIPANTS: Individuals aged 60 and older referred for insomnia complaints or suspected sleep apnea (N = 135). MEASUREMENTS: Tests included clinical interview, sleepiness scale, anxiety and depression scale, Insomnia Severity Index (ISI), Mini-Mental State Examination (MMSE), and overnight polysomnography, followed by multiple sleep latency tests. At the end of each of four nap opportunities, participants answered whether they had slept during the test. Nap underperception was defined as two or more unperceived naps. RESULTS: Of the 105 participants who napped at least twice, 42 (40%) did not perceive at least two naps. These participants had lower MMSE scores (P = .01) and were more likely to be taking benzodiazepines (P = .008) than the 63 participants who did not underperceive their naps but had similar demographic characteristics, sleep diagnoses, depression and anxiety scores, and polysomnography measures. Both groups had similarly short mean daytime sleep latencies (9.7 ± 4.5 minutes and 9.8 ± 3.7 minutes), but participants who underperceived their naps scored lower on the Epworth Sleepiness Scale (5.6 ± 4.0, vs 9.6 ± 4.8, P < .001). An ISI of 11 or greater, a MMSE score of 26 or less, and a sleepiness score of 8 or less were each independently associated with underperception of naps. The combination of these three factors yielded a positive predictive value of 93% and a negative predictive value of 71% for nap underperception. CONCLUSION: Older adults referred for sleep consultation with cognitive impairment and greater insomnia symptoms frequently underperceive naps, leading them to underestimate their level of sleepiness. In such cases, objective measures of daytime sleepiness would be better than the Epworth Sleepiness Scale.

The case view, a generic method of visualization of the case mix.

OBJECTIVE: There is a worldwide consensus to use the diagnosis related groups (DRG) to consider hospital activity. This tool leads to the production of tables with numbers (case mix), the interpretation of which is difficult. The issue is to translate these tables of numbers into an image named Case view. METHOD: It assimilates, in a way, each DRG to a "pixel", the set of the DRGs being an image, the case view. The methods consist of two phases: the first one is to define the reference set while the second one is to visualize data through the reference set. The "DRG-pixels" which constitute the reference set should be organized according to three criteria: medical/surgical, nosological and economic. RESULTS: This method is used to answer theoretical questions or to visualize activity at the level of a hospital or at the level of a department. It generates information of synthetic nature and ought to be used as a complement to existing methods. DISCUSSION: An important advantage of this method compared to the existing ones (DRGs listing, DRGs clustering, histograms em leader ) is that it presents data simultaneously at a global level (sets of DRGs) and at a local level (the DRG). CONCLUSION: We hope this method to be a supplementary step toward the creation of tools capable of eliciting the semantic content hidden in the medical data banks. The purpose of this paper is to explain the underlying general principles that define the graphic representation and to illustrate this model with the use of the French reference set.

Caseview: building the reference set.

There is a worldwide consensus for using the diagnosis related groups (DRG) when considering hospital activity. This tool leads to the production of tables of numbers (case mix), the interpretation of which is difficult. Therefore, methods aimed at facilitating this interpretation are needed. One of such methods is the case view, i.e. a graphical representation of the case mix. It reduces, in a way, each DRG to a "pixel", the set of the DRGs being an image (the case view). The reference set should be organized according to three criteria: medical/surgical, nosological and economic. This method can be used to answer theoretical questions or to visualize activity at the level of a hospital or at the level of a department. The purpose of this paper is to present important principles inherent in this graphic representation, both at the level of the method and at the level of the user.

Validation of the French version of the Pittsburgh Sleep Quality Index Addendum for posttraumatic stress disorder.

BACKGROUND: Sleep disturbances are one of the main complaints of patients with trauma-related disorders. The original Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A) is self-report instrument developed to evaluate posttraumatic stress disorder (PTSD)-specific sleep disturbances in trauma-exposed individuals. However, to date, the PSQI-A has not yet been translated nor validated in French. OBJECTIVE: THE PRESENT STUDY AIMS TO: a) translate the PSQI-A into French, and b) examine its psychometric properties. METHOD: Seventy-three adult patients (mean age=40.3 [SD=15.0], 75% females) evaluated in a specialized psychotraumatology unit completed the French versions of the PSQI-A, Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), and Impact Event Scale-Revised (IES-R). RESULTS: The French version of the PSQI-A showed satisfactory internal consistency, inter-item correlations, item correlations with the total score, convergent validity with PTSD and anxiety measures, and divergent validity with a depression measure. CONCLUSION: Our findings support the use of the French version of the PSQI-A for both clinical care and research. The French version of the PSQI-A is an important addition to the currently available instruments that can be used to examine trauma-related sleep disturbances among French-speaking individuals.

Evaluating OPTISAS, a visual method to analyse sleep apnea syndromes.

The sleep apnea syndrome is a real public health problem. Improving its diagnosis using the polysomnography is of huge importance. Optisas was a visual method allowing translating the polysomnographic data into a meaningful image. In a previous paper, it was shown to bring extra information in 62% of cases. Here its capacity for displaying information of the same relevance as the one got using the classical report of the polysomnography is studied. The main result is that this capacity is weak and seems to be present only to identify the obstructive sleep apnea syndrome. Moreover this study suggests to improve the standardization of the classical report in the framework of a quality insurance process.

Generalized Caseview applied to prostate cancer prognosis.

The interpretation of results of any study using large tables with series of numbers is always difficult. Generalized Case View Method (GCm) allows translating these tables of numbers into an image. The Method identifies each informational entity in the table with a 'pixel', forming what we call an 'infoxel'. The sum of all informational entities becomes an image, the Generalized Caseview. The method consists of two steps: the first one is to define the reference frame while the second is to visualize data through the reference frame. The 'infoxels' that constitute the reference frame should be organized according to three criteria: binary, nominal and ordinal. Here this method has been applied to visualize the results of a study about prostate cancer spread. This paper exemplifies the usefulness of associating a classical statistical tool with Generalized Caseview method to solve a biomedical problem.

Abnormal expression of M1/MUC5AC mucin in distal colon of patients with diverticulitis, ulcerative colitis and cancer.

The abnormal expression of gastric M1/MUC5AC mucin in precancerous lesions and colon cancer evidenced by immunohistochemistry led us to check for its presence in the mucus obtained directly from patients undergoing surgery for cancerous (adenocarcinoma) or inflammatory (diverticulitis or ulcerative colitis) diseases. In parallel, the authors quantified aberrant crypt foci (ACF) and their immunolabelling by M1/MUC5AC in mucosae of cancer and diverticulitis patients. Immuno-Radio-Metric Assay of M1/MUC5AC mucin developed by the authors was used to detect M1/MUC5AC mucin in the colonic mucus scraped from surgical specimens. M1/MUC5AC mucin was detected in the mucus of 51/69 (74%) patients with colon adenocarcinoma, versus 7/27 (26%) patients with diverticulitis (threshold: 30 units of M1 mucin per mg protein, area under ROC curve: 0.80). M1/MUC5AC was present in significantly (p < 0.001) larger amounts in the mucus of cancer versus diverticulitis patients. All (10/10) patients with ulcerative colitis tested showed levels above the threshold and their mucosae were strongly labelled with the anti-M1/MUC5AC antibody by immunohistochemistry. Patients with cancer exhibited 3 fold more ACF than those with diverticulitis, but no significant difference was observed in the mean size and M1/MUC5AC expression pattern of ACF between these two groups. The expression of M1/MUC5AC was in correlation with their size. In macroscopically normal mucosa, ACF were the most important source of M1/MUC5AC mucin. Testing of M1/MUC5AC can enhance the detection of precancerous lesions and colon cancer.

ICPCview: visualizing the International Classification of Primary Care.

This paper proposes a method to visualize the semantic content of data bases where the medical information is coded with the International Classification of Primary Care. The main idea is the identification of a pixel with a code and the conversion of all the data associated with these into an image the ICPCview. The method proceeds in two step, defining the reference frame and using this reference frame to visualize data. The reference frame is built by using a sign/diagnosis binary criterion, a seventeen category nosological criterion and an age ordinal criterion. The results are visualization of the signs and diagnosis of the ICPC according to gender, age and time period of the year. A limitation of the method lies in the fact that the result depends on the chosen reference frame. Further work has to be done with various reference frames and data. However the main point is that, when both the reference set of the image and of the mind of the user are built, the method is powerful at extracting the hidden content of a very large amount of data.