Exploring the use of Granger causality for the identification of chemical exposure based on physiological data.

Wearable sensors offer new opportunities for the early detection and identification of toxic chemicals in situations where medical evaluation is not immediately possible. We previously found that continuously recorded physiology in guinea pigs can be used for early detection of exposure to an opioid (fentanyl) or a nerve agent (VX), as well as for differentiating between the two. Here, we investigated how exposure to these different chemicals affects the interactions between ECG and respiration parameters as determined by Granger causality (GC). Features reflecting such interactions may provide additional information and improve models differentiating between chemical agents. Traditional respiration and ECG features, as well as GC features, were extracted from data of 120 guinea pigs exposed to VX (n = 61) or fentanyl (n = 59). Data were divided in a training set (n = 99) and a test set (n = 21). Minimum Redundancy Maximum Relevance (mRMR) and Support Vector Machine (SVM) algorithms were used to, respectively, perform feature selection and train a model to discriminate between the two chemicals. We found that ECG and respiration parameters are Granger-related under healthy conditions, and that exposure to fentanyl and VX affected these relationships in different ways. SVM models discriminated between chemicals with accuracy of 95% or higher on the test set. GC features did not improve the classification compared to traditional features. Respiration features (i.e., peak inspiratory and expiratory flow) were the most important to discriminate between different chemical's exposure. Our results indicate that it may be feasible to discriminate between chemical exposure when using traditional physiological respiration features from wearable sensors. Future research will examine whether GC features can contribute to robust detection and differentiation between chemicals when considering other factors, such as generalizing results across species.

Hallazgos oftalmológicos en pacientes con leucemia en una población colombiana / Ophthalmological findings in patients with leukaemia in a Colombian population

Objetivo Publicar las manifestaciones oculares en paciente con leucemia. Métodos Estudio observacional analítico de corte transversal, en pacientes con manifestaciones oculares por leucemia. Resultados Se evaluaron 14 ojos de 8 pacientes (5 mujeres y 3 varones) con leucemia. La edad promedio al diagnóstico de leucemia fue de 43 años (31-76 años). Seis ojos correspondían a pacientes con leucemia mieloide aguda (LMA), 4 ojos a pacientes con leucemia linfoide aguda (LLA), 2 ojos a pacientes con leucemia mieloide crónica (LMC) y 2 ojos a pacientes con leucemia de células peludas (LCP). Los hallazgos oculares primarios fueron: invasión coroidea en 12 ojos (85,7%), infiltración retiniana en 4 ojos (28,6%) y desórdenes neuroftalmológicos en 4 ojos (28,6%). La agudeza visual promedio mejoró de 0,689 a 0,449 logMAR (p 0,012) luego del tratamiento con quimioterapia sistémica e intratecal. De los 8 pacientes, 4 murieron debido a complicaciones de su enfermedad. Conclusiones Este es el primer artículo de múltiples manifestaciones oculares secundaria a leucemia en una población colombiana. Es importante tener en cuenta que este tipo de manifestaciones hacen parte de los síndromes de enmascaramiento por lo tanto es primordial hacer un diagnóstico y manejo precoz ya que en ocasiones está en riesgo la vida del paciente (AU)

Objective To report the ocular manifestations in patients with leukaemia. Methods This is a retrospective, descriptive and observational study in patients with ocular manifestations of leukaemia. Results A total of 14 eyes were evaluated corresponding to 8 patients (5 women and 3 men) with ocular manifestations of leukaemia. The mean age at diagnosis was 43 years (31-76 years). Six eyes corresponded to patients with acute myeloid leukaemia (AML), four eyes to acute lymphoid leukaemia (ALL), two eyes to chronic myeloid leukaemia (CML), and the remaining two belonged to patients with hairy cell leukaemia (HCL). The primary ocular findings were choroidal invasion in 12 eyes (85.7%), retinal infiltration in 4 eyes (28.6%), and neuro-ophthalmic disorders in 4 eyes (28.6%). The mean visual acuity improved from 0.689 to 0.449 (logMAR) (P=.012) after the systemic and intrathecal chemotherapy. Of the eight patients, four died from systemic complications of the underlying disease. Conclusions This is the first report of multiple ocular manifestations secondary to leukaemia in a Colombian population. It is important to keep in mind that this disease is included within the masquerade syndromes and that the ophthalmological findings that, while subtle, can also be devastating and be signs of a life-threatening disease (AU)

Ophthalmological findings in patients with leukaemia in a Colombian population. / Hallazgos oftalmológicos en pacientes con leucemia en una población colombiana.

OBJECTIVE: To report the ocular manifestations in patients with leukaemia. METHODS: This is a retrospective, descriptive and observational study in patients with ocular manifestations of leukaemia. RESULTS: A total of 14 eyes were evaluated corresponding to 8 patients (5 women and 3 men) with ocular manifestations of leukaemia. The mean age at diagnosis was 43 years (31-76 years). Six eyes corresponded to patients with acute myeloid leukaemia (AML), four eyes to acute lymphoid leukaemia (ALL), two eyes to chronic myeloid leukaemia (CML), and the remaining two belonged to patients with hairy cell leukaemia (HCL). The primary ocular findings were choroidal invasion in 12 eyes (85.7%), retinal infiltration in 4 eyes (28.6%), and neuro-ophthalmic disorders in 4 eyes (28.6%). The mean visual acuity improved from 0.689 to 0.449 (logMAR) (P=.012) after the systemic and intrathecal chemotherapy. Of the eight patients, four died from systemic complications of the underlying disease. CONCLUSIONS: This is the first report of multiple ocular manifestations secondary to leukaemia in a Colombian population. It is important to keep in mind that this disease is included within the masquerade syndromes and that the ophthalmological findings that, while subtle, can also be devastating and be signs of a life-threatening disease.

The implementation of an apnea-based perinatal stress calculator.

Early life stress in the neonatal intensive care unit (NICU) predisposes premature infants to adverse health outcomes. Although those patients experience frequent apneas and sleep-wake disturbances during their hospital stay, clinicians still rely on clinical scales to assess pain and stress burden. This study addresses the relationship between stress and apneic spells in NICU patients to implement an automatic stress detector. EEG, ECG and SpO2 were recorded from 40 patients for at least 3 hours and the stress burden was assessed using the Leuven Pain Scale. Different logistic regression models were designed to detect the presence or the absence of stress based on the signals reactivity to each apneic spell. The classification shows that stress can be detected with an area under the curve of 0.94 and a misclassification error of 19.23%. These results were obtained via SpO2 dips and EEG regularity. These findings suggest that stress deepens the physiological reaction to apneas, which could ultimately impact the neurological and behavioral development.

All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth.

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been demonstrated in gastric carcinoma and has opened new perspectives to develop targeted therapy. In this study, we evaluated the effects of all-trans-retinoic acid (ATRA) on CSCs in human gastric carcinoma. ATRA effects were evaluated on the proliferation and tumorigenic properties of gastric carcinoma cells from patient-derived tumors and cell lines in conventional 2D cultures, in 3D culture systems (tumorsphere assay) and in mouse xenograft models. ATRA inhibited both tumorspheres initiation and growth in vitro, which was associated with a cell-cycle arrest through the upregulation of cyclin-dependent kinase (CDK) inhibitors and the downregulation of cell-cycle progression activators. More importantly, ATRA downregulated the expression of the CSC markers CD44 and ALDH as well as stemness genes such as Klf4 and Sox2 and induced differentiation of tumorspheres. Finally, 2 weeks of daily ATRA treatment were sufficient to inhibit gastric tumor progression in vivo, which was associated with a decrease in CD44, ALDH1, Ki67 and PCNA expression in the remaining tumor cells. Administration of ATRA appears to be a potent strategy to efficiently inhibit tumor growth and more importantly to target gastric CSCs in both intestinal and diffuse types of gastric carcinoma.

Probabilistic cardiac and respiratory based classification of sleep and apneic events in subjects with sleep apnea.

Current clinical standards to assess sleep and its disorders lack either accuracy or user-friendliness. They are therefore difficult to use in cost-effective population-wide screening or long-term objective follow-up after diagnosis. In order to fill this gap, the use of cardiac and respiratory information was evaluated for discrimination between different sleep stages, and for detection of apneic breathing. Alternative probabilistic visual representations were also presented, referred to as the hypnocorrogram and apneacorrogram. Analysis was performed on the UCD sleep apnea database, available on Physionet. The presence of apneic events proved to have a significant impact on the performance of a cardiac and respiratory based algorithm for sleep stage classification. WAKE versus SLEEP discrimination resulted in a kappa value of κ = 0.0439, while REM versus NREM resulted in κ = 0.298 and light sleep (N1N2) versus deep sleep (N3) in κ = 0.339. The high proportion of hypopneic events led to poor detection of apneic breathing, resulting in a kappa value of κ = 0.272. While the probabilistic representations allow to put classifier output in perspective, further improvements would be necessary to make the classifier reliable for use on patients with sleep apnea.

Helicobacter pylori infection and gastric carcinoma.

Helicobacter pylori infection is considered to be the main cause of gastric cancer and the most frequent infection-induced cancer. H. pylori is a heterogeneous species which can harbour pathogenic factors such as a cytotoxin, a pathogenicity island (cag) encoding a type 4 secretion system, and the first bacterial oncoprotein, CagA. This oncoprotein appears to be involved in the carcinogenic process in addition to the inflammation generated. This process may concern either local progenitors via an epithelial-mesenchymal transition, or recruited bone marrow-derived mesenchymal cells. There are also environmental factors such as iron deficiency or high-salt diets which interact with the bacterial factors to increase the risk of gastric cancer as well as genetic polymorphism of certain cytokines, e.g. IL-Iß. Recent data suggest that a break in coevolution of a particular phylogeographic lineage of H. pylori and its usual host may also be a risk factor. Studies are currently being performed to assess the feasibility of organized H. pylori eradication programmes to prevent gastric cancer.

Helicobacter pylori infection and stem cells at the origin of gastric cancer.

Helicobacter pylori infection is now recognized as the main and specific infectious cause of cancer in the world. It is responsible for gastric adenocarcinomas of both intestinal and diffuse types, which are the long-term consequences of the chronic infection of the gastric mucosa. Case-control studies have shown an association between the two, recognized as early as 1994 and further substantiated by interventional studies in which H. pylori eradication has led to the prevention of at least part of the gastric cancers. Experimental studies have highlighted the role of bone marrow-derived cells (BMDCs) and particularly mesenchymal stem cells, in the neoplastic process in about a quarter of the cases and possibly an epithelial-mesenchymal transition (EMT) in the other cases. Different studies have confirmed that chronic infection with H. pylori induces a chronic inflammation and subsequent damage of the gastric epithelial mucosa, leading to BMDC recruitment. Once recruited, these cells home and differentiate by cell-cell fusion with local gastric epithelial cells, bearing local stem cell failure and participating in tissue regeneration. The context of chronic infection and inflammation leads to an EMT and altered tissue regeneration and differentiation from both local epithelial stem cells and BMDC. EMT induces the emergence of CD44+ cells possessing mesenchymal and stem cell properties, resulting in metaplastic and dysplastic lesions to give rise, after additional epigenetic and mutational events, to the emergence of cancer stem cells (CSCs) and adenocarcinoma.

Helicobacter pylori generates cells with cancer stem cell properties via epithelial-mesenchymal transition-like changes.

Helicobacter pylori infection is the major risk factor for gastric adenocarcinoma. The link with gastric adenocarcinoma is partly due to the H. pylori CagA oncoprotein. CagA is responsible for a particular cell phenotype in vitro, the 'hummingbird' phenotype, that corresponds to an elongation of the cells, mimicking an epithelial-mesenchymal transition (EMT). EMT participates in the carcinogenesis process, and is involved in the generation of cancer stem cells (CSCs). However, its involvement in gastric carcinogenesis has yet not been studied. Therefore, the aim of this study was to determine the role of H. pylori in EMT and in the emergence of gastric CSCs. For this purpose, gastric epithelial cells were cocultured with a cagA-positive H. pylori strain or its isogenic-deleted mutants or were transfected with CagA expression vectors. Study of the expression of epithelial and mesenchymal markers showed that H. pylori, via CagA, is responsible for an EMT phenotype associated with an increase in mesenchymal markers as well as CD44 expression, a known gastric CSC marker. Moreover, infection led to an increased ability to migrate, to invade and to form tumorspheres. Cell sorting experiments showed that only the CD44(high) cells induced by H. pylori infection displayed the mesenchymal phenotype and CSC properties in vitro, and had higher tumorigenic properties than CD44(low) cells in xenografted mice. Immunohistochemistry analyses on human and mouse gastric mucosa tissue samples confirmed a high expression of CD44 and mesenchymal markers in H. pylori-infected cases, and in gastric dysplasia and carcinoma. All of these data suggest that H. pylori, via CagA, unveils CSC-like properties by induction of EMT-like changes in gastric epithelial cells.

Early respiratory dysfunction as a biomarker for epileptic encephalopathy.

OBJECTIVES: West syndrome is an epileptic encephalopathy starting in infancy with almost continuous interictal epileptic activity, so-called hypsarrhythmia pattern, and therefore is an interesting model for investigating the effect of interictal epileptic activity on autonomic function. It is known that autonomic dysfunction contributes to morbidity and mortality in epilepsy. Our aim is to investigate the effect of interictal epileptic activity in West syndrome on respiratory control. MATERIALS AND METHODS: Interictal single-lead ECG signals were extracted from 24-h video-EEG recordings in 10 children suffering from West syndrome and 14 control subjects. RR interval time series were calculated, and respiration was derived from the ECG signal. ECG-derived respiration (EDR) signals were computed and time and frequency domain parameters were extracted to characterize the respiration pattern. RESULTS: In time domain, the standard deviation of the EDR signal is significantly lower in patients with West syndrome compared to control subjects. This finding is an indication of a less variable respiratory rate. In frequency domain, we analyzed the mean power spectrum for the EDR. In patients with West syndrome, there is more activity at the lower frequencies considered to be a risk factor for apneas. Second, there is an attenuated peak at the higher frequency band where normal respiratory rate is to be found, indicating an abnormal breathing pattern. CONCLUSIONS: Our results show that there is a clear dysfunction in autonomic respiratory control in patients with West syndrome, in between the typical ictal epileptic spasms, compared to control subjects. Respiration is more fixed and contains a higher risk of apneas.

Host-interactive genes in Amerindian Helicobacter pylori diverge from their Old World homologs and mediate inflammatory responses.

Helicobacter pylori is the dominant member of the gastric microbiota and has been associated with an increased risk of gastric cancer and peptic ulcers in adults. H. pylori populations have migrated and diverged with human populations, and health effects vary. Here, we describe the whole genome of the cag-positive strain V225d, cultured from a Venezuelan Piaroa Amerindian subject. To gain insight into the evolution and host adaptation of this bacterium, we undertook comparative H. pylori genomic analyses. A robust multiprotein phylogenetic tree reflects the major human migration out of Africa, across Europe, through Asia, and into the New World, placing Amerindian H. pylori as a particularly close sister group to East Asian H. pylori. In contrast, phylogenetic analysis of the host-interactive genes vacA and cagA shows substantial divergence of Amerindian from Old World forms and indicates new genotypes (e.g., VacA m3) involving these loci. Despite deletions in CagA EPIYA and CRPIA domains, V225d stimulates interleukin-8 secretion and the hummingbird phenotype in AGS cells. However, following a 33-week passage in the mouse stomach, these phenotypes were lost in isolate V225-RE, which had a 15-kb deletion in the cag pathogenicity island that truncated CagA and eliminated some of the type IV secretion system genes. Thus, the unusual V225d cag architecture was fully functional via conserved elements, but the natural deletion of 13 cag pathogenicity island genes and the truncation of CagA impaired the ability to induce inflammation.

Carbapenem-resistant Enterobacter cloacae and the emergence of metallo-beta-lactamase-producing strains in a third-level hospital (Santiago de Compostela, NW Spain).

The purpose of this paper was to investigate the occurrence of carbapenem-resistant Enterobacter cloacae in our institution, to detect the carbapenemase-associated resistance and to determine the genetic relatedness of the isolates. Species identification and antimicrobial susceptibility testing were performed using the Vitek 2 system and Etest. Multiplex polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA) was used for the detection of extended-spectrum beta-lactamase (ESBL)-producers. The bla (IMP) and bla (VIM) genes were amplified by PCR and sequenced. The DiversiLab System was used for strain-typing. During the period 2006-2008, 12 different isolates of carbapenem-resistant E. cloacae (2.3 %) were recovered in our laboratory. Only two positive isolates for the bla (VIM) gene were detected. The minimum inhibitory concentration (MIC) values were higher for all carbapenems in the group of non-metallo-beta-lactamase (MBL)-producers. All isolates showed MIC values

Multiscale deformable registration for dual-energy x-ray imaging.

Dual-energy (DE) imaging of the chest improves the conspicuity of subtle lung nodules through the removal of overlying anatomical noise. Recent work has shown double-shot DE imaging (i.e., successive acquisition of low- and high-energy projections) to provide detective quantum efficiency, spectral separation (and therefore contrast), and radiation dose superior to single-shot DE imaging configurations (e.g., with a CR cassette). However, the temporal separation between high-energy (HE) and low-energy (LE) image acquisition can result in motion artifacts in the DE images, reducing image quality and diminishing diagnostic performance. This has motivated the development of a deformable registration technique that aligns the HE image onto the LE image before DE decomposition. The algorithm reported here operates in multiple passes at progressively smaller scales and increasing resolution. The first pass addresses large-scale motion by means of mutual information optimization, while successive passes (2-4) correct misregistration at finer scales by means of normalized cross correlation. Evaluation of registration performance in 129 patients imaged using an experimental DE imaging prototype demonstrated a statistically significant improvement in image alignment. Specific to the cardiac region, the registration algorithm was found to outperform a simple cardiac-gating system designed to trigger both HE and LE exposures during diastole. Modulation transfer function (MTF) analysis reveals additional advantages in DE image quality in terms of noise reduction and edge enhancement. This algorithm could offer an important tool in enhancing DE image quality and potentially improving diagnostic performance.

Study of Helicobacter pullorum proinflammatory properties on human epithelial cells in vitro.

BACKGROUND AND AIMS: Helicobacter pullorum is an enterohepatic Helicobacter species of avian origin detected in patients with acute diarrhoea and inflammatory bowel disease. The aim of the present study was to determine whether H pullorum exerts a direct effect on human intestinal epithelial cells in vitro and to characterise the bacterial mechanisms and the signalling pathways involved. MATERIALS AND METHODS: The proinflammatory properties of H pullorum from human and avian origins were measured on human gastric (AGS) and intestinal (CaCo-2 and HT-29) epithelial cell lines after co-culture with different H pullorum strains, and the extent of nuclear factor-kappaB (NF-kappaB) involvement was determined. RESULTS: All of the H pullorum strains tested stimulated interleukin 8 (IL8) secretion by the three cell lines. Similar results were obtained with heat-killed H pullorum. Incubation of cells with filtered H pullorum culture supernatants did not stimulate IL8 secretion. The same observation was made when bacterial adherence was inhibited by Transwell inserts. H pullorum induced NF-kappaB activation and rapid nuclear translocation as demonstrated by immunofluorescent staining and cellular fractionation. NF-kappaB involvement was confirmed by using the specific inhibitor SN50 and small interfering RNA (siRNA) which abolished H pullorum-induced IL8 production. CONCLUSIONS: H pullorum strains stimulate IL8 secretion by human gastric and intestinal epithelial cell lines. This effect requires bacterial adherence and probably lipopolysaccharides, and is mediated by NF-kappaB signalling. The present study strengthens the argument that H pullorum is a potent human pathogen and highlights its putative role in acute and chronic digestive diseases such as inflammatory bowel disease.

The influence of water content of hydrogel contact lenses when fitting patients with 'tear film deficiency'.

THe fitting of patients presenting a deficient tear film with hydrogel contact lenses offers a challenge to the professional who must choose between materials having either a low or a high water content. Conflicting conclusions from previous studies concerning the better option led the authors to design a single-centre, double masked, clinical study. Twenty-six subjects deemed to have 'tear film deficiency' were fitted with a low water content hydrogel lens on one eye and a high water content one on the other eye. Each subject wore the lenses on a daily wear basis (about 10 hours a day) for 30 days. A detailed questionnaire about subjective considerations, such as comfort and ocular appearance, was completed by the subjects at the end of every day of contact lens wear. The data obtained from these questionnaires and those recorded at three follow-up visits led to the final conclusions. THe questionnaires showed no statistically significant difference between the two eyes in dryness sensation, redness, light sensitivity, blurred vision or overall comfort. During the follow-up visits, no observed sign showed a clinically significant difference between the two eyes. Accordingly, the authors conclude that the water content of hydrogel lens is not a key factor when fitting hydrogel lenses to patients with 'tear film deficiency'.

Analytical and clinical evaluation of a procedure for measuring CA 15-3 in the IMx analyser.

CA 15-3 is the most widely used tumour marker in the follow-up of patients with breast cancer. Its postoperative blood level is closely related to the response to the treatment applied and to the evolution of the disease. In this study, we assessed both the clinical and analytical features of a new microparticle enzyme immunoassay for CA 15-3 quantification in the Abbott IMx system. In the precision study, the coefficients of variation within runs, between runs and between laboratories were 3.5, 5.1 and 6.5% or less, respectively. The analytical sensitivity of the assay was 0.11 U/ml. Linear regression analyses of the IMx CA 15-3 assay with the Centocor and CIS CA 15-3 RIAs gave correlation coefficients of 0.88 and 0.95, respectively. The upper limit of the reference range, obtained from serum of healthy women, was 27.3 U/ml, while the ROC curve analysis for patients with active breast cancer compared to patients with no evidence of the disease gave an optimum cutoff of 33 U/ml (sensitivity 0.76 and specificity 0.87). The overall agreement of the three methods was over 90%.

Estudio radiológico de doble contraste del instestino delgado en todas las edades: presentación de 100 pacientes

Presentamos un estudio prospectivo en 100 pacientes, 60 adultos y 40 niños, realizado en los Hospitales San Ignacio e Infantil de la Misericordia; en quienes se practicó un examen radiológico de Doble Contraste del Intestino Delgado. Informamos sobre la técnica y los hallazgos radiológicos, clínicos e histológicos. Se demostró la ventaja sobre el estudio tradicional y su alta sensibilidad, especificidad y poder predicitvo positivo