Ras-Erk signaling induces phosphorylation of human TLE1 and downregulates its repressor function.

Signaling mediated by the Ras-extracellular signal-regulated kinase (Erk) pathway often leads to the phosphorylation of transcriptional regulators, thereby modulating their activity and causing concerted changes in gene expression. In Drosophila, the induction of multiple Ras-Erk pathway target genes depends on prior phosphorylation of the general co-repressor Groucho, a modification that downregulates its repressive function. Here, we show that TLE1, one of the four human Groucho orthologs, is similarly phosphorylated in response to Ras-Erk pathway activation, and that this modification attenuates its capacity to repress transcription. Specifically, unphosphorylated TLE1 dominantly suppresses the induction of Ras-Erk pathway target genes in cultured human cells, and the expression of an unphosphorylatable TLE1 derivative causes severe phenotypes in a transgenic Drosophila model system, whereas a phosphomimetic variant of TLE1 exerts only negligible effects. We present data indicating that TLE1 is rapidly excluded from the nucleus following epidermal growth factor receptor pathway activation, an effect that likely accounts for its inability to mediate effective repression under such conditions. Significantly, we find that unphosphorylated TLE1 blocks oncogenic phenotypes induced by mutated H-Ras in human mammary cells, both in vitro and following their implantation in mice. Collectively, our data strongly indicate that phosphorylation of TLE family members and the consequent downregulation of their repressor function is a key conserved step in the transcriptional responses to Ras-Erk signaling, and possibly a critical event in the tumorigenic effects caused by excessive Ras-Erk pathway activity.

Brain activation associated with practiced left hand mirror writing.

Mirror writing occurs in healthy children, in various pathologies and occasionally in healthy adults. There are only scant experimental data on the underlying brain processes. Eight, right-handed, healthy young adults were scanned (BOLD-fMRI) before and after practicing left-hand mirror-writing (lh-MW) over seven sessions. They wrote dictated words, using either the right hand with regularly oriented writing or lh-MW. An MRI compatible stylus-point recording system was used and online visual feedback was provided. Practice resulted in increased speed and readability of lh-MW but the number of movement segments was unchanged. Post-training signal increases occurred in visual, right lateral and medial premotor areas, and in right anterior and posterior peri-sylvian areas corresponding to language areas. These results suggest that lh-MW may constitute a latent ability that can be reinstated by a relatively brief practice experience. Concurrently, right hemisphere language processing areas may emerge, reflecting perhaps a reduction in trans-hemispheric suppression.

Exertional muscle pain in familial Mediterranean fever patients evaluated by MRI and 31P magnetic resonance spectroscopy.

AIM: To evaluate the effect of physical activity on the structural, morphological, and metabolic characteristics of the gastrocnemius muscle in familial Mediterranean fever (FMF) patients, utilizing quantitative (31)P magnetic resonance spectroscopy (MRS), in order to elucidate the mechanism of their exertional leg pain. MATERIALS AND METHODS: Eleven FMF patients suffering from exertional leg pain (eight male, three female; mean age 33 years) and six healthy individuals (three male, three female; mean age 39 years) constituted the control group. All of the participants underwent magnetic resonance imaging (MRI) and non-selective (31)P MRS (3 T) of the leg muscles before and after graded exercise on a treadmill. Phosphocreatine (PCr):inorganic phosphate (Pi), PCr:adenosine triphosphate (ATP) ratios and the intracellular pH of the leg muscles were measured using (31)P MRS. RESULTS: For both groups, normal muscle mass with no signal alterations was observed on the MRI images after exercise. The normal range of pre- and post- exercise MRS muscle parameters was observed in both groups. However, the intracellular pH post-exercise, was significantly higher (less acidic) in the FMF group compared to the control group [pH (FMF) = 7.03 ± 0.02; pH (control) 7.00 ± 0.02; p < 0.0006]. CONCLUSIONS: The finding of a less prominent, post-exercise acidification of the gastrocnemius muscle in this FMF patient group suggests a forme fruste of glycogenosis. This preliminary observation should be further investigated in a future, larger-scale study.

Exertional leg pain as a manifestation of occult spondyloarthropathy in familial Mediterranean fever: an MRI evaluation.

OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever, peritonitis, arthritis, and pleuritis, caused by neutrophil-induced sterile serositis. Another clinical manifestation in patients with FMF is exertional leg and ankle pain that appears after minor exercise, for which the underlying mechanism is obscure. The purpose of the current study was to feature distal leg changes in FMF patients complaining of exertional leg pain, using magnetic resonance imaging (MRI). METHODS: Eleven patients with FMF who suffer from exertional leg pain (eight males, three females; mean age 33 years) and six unaffected controls (three males, three females; mean age 39 years) underwent MRI (3 T) of the ankle, including conventional T1 and T2 with fat saturation sequences, before and after graded exercise on a treadmill. Clinical and genetic data and sacroiliac radiographs were obtained. RESULTS: Ten patients (91%) with FMF but none of the control group had signs compatible with enthesitis of the Achilles tendon, long plantar ligament, or the plantar fascia (including enthesophytes, erosions, and bone marrow oedema). Nine patients (80%) had radiographic signs of sacroiliitis on the pelvic radiograph. CONCLUSIONS: Exertional leg pain in FMF patients, shown to be associated with signs of enthesopathy on imaging, may be included within the spectrum of spondyloarthropathy.

Psychosocial abilities of first-year medical students participating in a clinical communication course.

BACKGROUND: Responding to psychosocial needs of patients is an important element of medical practice and is dependent on the psychosocial abilities of the physician. One of the aims of teaching doctor-patient communication in medical schools is to strengthen these qualities. We assessed changes in the psychosocial abilities of first-year medical students participating in a year-long clinical communication course. METHODS: Sixty-eight first-year medical students and 49 students from the Medical Laboratories School (control group) participated in the study. The students completed, once each at the beginning (October) and at the end (July) of the course, a structured questionnaire that included a psychosocial abilities measure and sociodemographic details. RESULTS: No significant differences were found between the two groups of students regarding their sociodemographic characteristics. Furthermore, the medical students and the control group did not differ significantly in their psychosocial abilities mean scores at the beginning of the communication course (baseline). At the end of the course, a significant improvement in mean scores was found among medical students compared with an insignificant decline among the control group. CONCLUSION: Participation in an extensive clinical doctor-patient communication course guided by multidisciplinary teams may strengthen psychosocial abilities of medical students. The study needs to be replicated with a larger sample size.

Further confirmation of the psychometric properties of responses to the psychological medicine inventory -student version.

CONTEXT: The Psychological Medicine Inventory (PMI) was first developed to measure physicians' reported interest level, confidence and perceived ability to address the psychological aspects of patient care. A student version of this scale has since been proposed (PMI-S). OBJECTIVE: To further examine the psychometric properties of responses to this student version and to confirm a 2-factor response structure. METHODS: A total of 213 first-year medical students at Ben-Gurion University of the Negev participated in this study. They completed the PMI-S (translated into Hebrew) and a socio-demographic questionnaire. The viability of the 2-factor structure of PMI-S responses was assessed using confirmatory factor analysis (CFA). FINDINGS: Consistent with the original English language version, CFA supported a 2-factor solution (i.e., psychological abilities and psychological sensitivity). All goodness-of-fit indices were found to be within ideal parameters. DISCUSSION AND CONCLUSIONS: Results of this study suggest that the PMI-S can be used to assess psychosocial competence and abilities of medical students and to evaluate the effectiveness of psycho-educational programs aimed at improving their psychosocial abilities.

In vivo molecular imaging of met tyrosine kinase growth factor receptor activity in normal organs and breast tumors.

Molecular imaging techniques allow visualization of specific gene products and their physiological processes in living tissues. In this study, we present a new approach for molecular imaging of endogenous tyrosine kinase receptor activity. Met and its ligand hepatocyte growth factor scatter factor (HGF/SF), which mediate mitogenicity, tumorigenicity, and angiogenesis, were used as a model. HGF/SF and Met play a significant role in the pathogenesis and biology of a wide variety of human epithelial cancers and, therefore, may serve as potential targets for cancer prognosis and therapy. We have shown previously that in vitro activation of Met by HGF/SF increases oxygen consumption. In this study, we demonstrate that Met activation in vivo by HGF/SF alters the hemodynamics of normal and malignant Met-expressing tissues. Tumor-bearing BALB/C mice were i.v. injected with HGF/SF and imaged using magnetic resonance imaging (MRI) and Doppler ultrasound. Organs and tumors expressing high levels of Met showed the most substantial alteration in blood oxygenation levels as measured by blood oxygenation level depended (BOLD)-MRI. No significant alteration was observed in tumors or organs that does not express Met. In the liver, which expresses high levels of Met, MRI signal alteration of about 60% was observed. In the kidneys, signal alteration was approximately 30%, and no change was observed in muscles. The extent of MRI signal alteration was also in correlation with HGF/SF doses. Injection of 7 and 170 ng/g body weight resulted in signal alteration of 5% and 30%, respectively, in tumors. Doppler ultrasound measurements demonstrated that these MRI changes are at least partially attributable to altered blood flow. These hemodynamic alterations, measured by MRI and Doppler ultrasound, were used in this study for the molecular imaging of Met activity in vivo. This novel molecular imaging technique may be used for in vivo diagnosis, prognosis, and therapy of Met-expressing tumors.

Vacuolating megalencephalic leukoencephalopathy in 12 Israeli patients.

Leukodystrophy with macrocephaly as the main features of infantile neurodegenerative disease are characteristics of Canavan's disease, L-2-hydroxyglutaric aciduria, type I glutaric aciduria, and Alexander's disease. Also occasionally described are occidental congenital muscular dystrophy, G(M)2-gangliosidosis, metachromatic leukodystrophy, Krabbe's disease, and mucopolysaccharidosis. Since 1995, over 60 patients with a new syndrome, vacuolating megalencephalic leukoencephalopathy, have been described. The syndrome is characterized by macrocephaly, a slowly progressive clinical course of ataxia, spastic paraparesis, and seizure disorder with relatively spared cognition. Unlike other leukodystrophies with macrocephaly (except Alexander's disease), no metabolic marker has been found. We describe a similar group of 12 patients from two different Jewish ethnic origins in whom consanguinity is prominent. These patients have neuroimaging features and magnetic resonance spectroscopy findings indicating that there is an initial increase in white-matter edema with subsequent cystic formation. Consistent with loss of tissue in these areas, brain metabolites are reduced. The familial incidence in this group of patients is suggestive of autosomal-recessive inheritance.

The dynamics of object-selective activation correlate with recognition performance in humans.

To investigate the relationship between perceptual awareness and brain activity, we measured both recognition performance and fMRI signal from object-related areas in human cortex while images were presented briefly using a masking protocol. Our results suggest that recognition performance is correlated with selective activation in object areas. Selective activation was correlated to object naming when exposure duration was varied from 20 to 500 milliseconds. Subjects' recognition during identical visual stimulation could be enhanced by training, which also increased the fMRI signal. Overall, the correlation between recognition performance and fMRI signal was highest in occipitotemporal object areas (the lateral occipital complex).

Continuing medical education and primary physicians' job stress, burnout and dissatisfaction.

OBJECTIVES: The association between opportunities for continuing medical education (CME) and primary physicians' job stress, burnout and job dissatisfaction has not been investigated. It was hypothesized that participation in CME activities and perceived opportunities at work for keeping up-to-date with medical and professional developments would be correlated negatively with job stress and burnout, and positively with job satisfaction. METHOD: 309 primary care physicians (183 family physicians and 126 paediatricians) employed in health maintenance organizations in Israel responded to a mailed questionnaire. The independent variables were the extent of engagement in CME activities and perceived opportunities at work for professional updating. The dependent variables were job stress, burnout and job satisfaction. Multiple regression analyses were employed. RESULTS: After controlling for age, sex and professional status, participation in CME activities was associated negatively with job stress and positively with job satisfaction, among family physicians. Among paediatricians, CME was associated negatively with burnout. Perceived opportunities for professional updating were associated negatively with burnout and (marginally) with stress among family physicians, and negatively with stress and positively with satisfaction among paediatricians. A third of the paediatricians and a quarter of the family physicians wanted to increase their involvement in CME. DISCUSSION: In this cross-sectional study, causality cannot be established and the CME measures should be refined. However, the results are consistent with the study's hypotheses and suggest that opportunities for CME and professional updating may reduce physicians' job distress and dissatisfaction.

Association between burnout at work and leukocyte adhesiveness/aggregation.

OBJECTIVE: This study examined whether burnout at work is associated with leukocyte adhesiveness/aggregation (LAA), a phenomenon known to be affected by stress. METHODS: The LAA levels of 179 employees (68 men and 111 women) of Tel Aviv University were determined when the employees underwent their annual routine medical checkup. Blood pressure and toxic chemical exposure were also measured, and background data were retrieved from medical records. Information on burnout and somatic complaints (known to be a general marker of stress) was collected through a self-report questionnaire. RESULTS: Total burnout and each of its subcomponents, emotional exhaustion, chronic fatigue, and cognitive weariness, was significantly associated with LAA levels, even after controlling for age, sex, and educational level. Burnout and somatic complaints intercorrelated positively, but somatic complaints were not significantly associated with LAA levels before or after controlling for the above possible confounders. CONCLUSIONS: Burnout was positively associated with LAA levels. This finding is consistent with the growing evidence of the negative impact of burnout on physical health. The lack of an association between somatic complaints and LAA levels reinforces the claim that burnout and stress are two different concepts.

Correlation of work structure and job satisfaction among Israeli family physicians.

BACKGROUND: Physicians need a professional environment that is conducive to efficient and satisfying work. Little has been published about the effect of work structure on the satisfaction that family physicians derive from their work. OBJECTIVES: To assess the structure and the positive and negative job components of family physicians in Israel, as well as the effect of these components on their satisfaction with their work. METHODS: A questionnaire was sent to a random selection of members of the Israel Society of Family Physicians (n = 225). RESULTS: Altogether 183 questionnaires were returned. Specialist family doctors, practice medical directors and salaried doctors were involved in more activities than non-specialist doctors, trainees and self-employed doctors. Overall satisfaction was highest for specialists and lowest for non-specialists. Work overload, insufficient resources and abundant paperwork were most frequently cited as negative work components. The opportunity to utilize medical knowledge, challenging work and work variety scored highest as positive components. CONCLUSIONS: The more professionally active physicians were also the more satisfied. Clinical work and teaching provided the most satisfaction, while administrative work and lack of time were the main causes of dissatisfaction.

Differential processing of objects under various viewing conditions in the human lateral occipital complex.

The invariant properties of human cortical neurons cannot be studied directly by fMRI due to its limited spatial resolution. Here, we circumvented this limitation by using fMR adaptation, namely, reduction of the fMR signal due to repeated presentation of identical images. Object-selective regions (lateral occipital complex [LOC]) showed a monotonic signal decrease as repetition frequency increased. The invariant properties of fMR adaptation were studied by presenting the same object in different viewing conditions. LOC exhibited stronger fMR adaptation to changes in size and position (more invariance) compared to illumination and viewpoint. The effect revealed two putative subdivisions within LOC: caudal-dorsal (LO), which exhibited substantial recovery from adaptation under all transformations, and posterior fusiform (PF/LOa), which displayed stronger adaptation. This study demonstrates the utility of fMR adaptation for revealing functional characteristics of neurons in fMRI studies.

Evaluation of an occupational health education program among 11th grade students.

BACKGROUND: There is a paucity of publications on occupational health as part of the educational curricula in high schools. We investigated the extent to which a new occupational health education program for 11th graders succeeded in achieving changes in their knowledge and attitudes. METHODS: Six classrooms were randomly assigned to either 96 participating students or to a control group (n = 100) that did not participate. Data on knowledge, attitudes, and beliefs were collected before and 4 months after completion of the course by means of an anonymous self-reported questionnaire. One point was assigned to each answer that was either correct or in the desired direction. Scoring was measured by adding up the points and then converting the total into a scale of 100. RESULTS: The experimental group had a statistically higher mean score (from 24.56 to 80.74) after completing the course. The control group had low scores at both time 1 (20.15) and time 2 (17.00). At least 50% more students of the experimental group gave correct answers after the course, while there was no such change in the control group. CONCLUSIONS: Our findings indicate that occupational health learning can occur in the secondary school setting and confirm the program's effectiveness in achieving desired changes in the immediate outcome of knowledge, attitudes, and beliefs in different areas of occupational health. The subject of occupational health is a topic with relevance to larger educational objectives and policies. In many countries all over the world as well as in Israel, this curriculum can potentially be integrated into the body of the current instruction of "Life Abilities," which are courses that cover topics that prepare the youngsters for adult lifestyles.

Association between somatic symptoms and 24-hour ambulatory blood pressure levels.

OBJECTIVE: To clarify whether somatic complaints in healthy normotensive men are associated with differential 24-hour blood pressure and heart rate measures. METHOD: Twenty-four-hour ambulatory systolic and diastolic blood pressure was monitored in 114 healthy normotensive men, aged 28 to 63 years, engaged in similar physical work. Means were calculated for each hour, for the whole 24-hour period, and for daytime, nighttime, and work time. Subjects were interviewed about somatic complaints, demographic data, and health habits, and body mass index was measured. RESULTS: After controlling for possible confounders, a positive association was found between the somatic complaint score and 24-hour, diurnal, and work-time systolic blood pressure (p = .014, p = .007, and p = .008, respectively). The association with casual systolic blood pressure was of borderline significance (p = .089). There was a positive trend, which did not reach statistical significance, in the relationship between somatic complaint score and all measures of diastolic blood pressure. Diurnal, 24-hour, and work-time heart rates were highest in the subjects with the highest somatic scores (p < .01 for all trends). CONCLUSIONS: In healthy normotensive men, somatic complaints are associated with an increased cardiovascular load. The effects of this increase on long-term cardiovascular morbidity and mortality are uncertain and warrant additional study.

Cue-invariant activation in object-related areas of the human occipital lobe.

The extent to which primary visual cues such as motion or luminance are segregated in different cortical areas is a subject of controversy. To address this issue, we examined cortical activation in the human occipital lobe using functional magnetic resonance imaging (fMRI) while subjects performed a fixed visual task, object recognition, using three different primary visual cues: motion, texture, or luminance contrast. In the first experiment, a region located on the lateral aspect of the occipital lobe (LO complex) was preferentially activated in all 11 subjects both by luminance and motion-defined object silhouettes compared to full-field moving and stationary noise (ratios, 2.00+/-0.19 and 1.86+/-0.65, respectively). In the second experiment, all subjects showed enhanced activation in the LO complex to objects defined both by luminance and texture contrast compared to full-field texture patterns (ratios, 1.43+/-0.08 and 1.32+/-0.08, respectively). An additional smaller dorsal focus that exhibited convergence of object-related cues appeared to correspond to area V3a or a region slightly anterior to it. These results show convergence of visual cues in LO and provide strong evidence for its role in object processing.

A sequence of object-processing stages revealed by fMRI in the human occipital lobe.

Functional magnetic resonance imaging was used in combined functional selectivity and retinotopic mapping tests to reveal object-related visual areas in the human occipital lobe. Subjects were tested with right, left, up, or down hemivisual field stimuli which were composed of images of natural objects (faces, animals, man-made objects) or highly scrambled (1,024 elements) versions of the same images. In a similar fashion, the horizontal and vertical meridians were mapped to define the borders of these areas. Concurrently, the same cortical sites were tested for their sensitivity to image-scrambling by varying the number of scrambled picture fragments (from 16-1,024) while controlling for the Fourier power spectrum of the pictures and their order of presentation. Our results reveal a stagewise decrease in retinotopy and an increase in sensitivity to image-scrambling. Three main distinct foci were found in the human visual object recognition pathway (Ungerleider and Haxby [1994]: Curr Opin Neurobiol 4:157-165): 1) Retinotopic primary areas V1-3 did not exhibit significant reduction in activation to scrambled images. 2) Areas V4v (Sereno et al., [1995]: Science 268:889-893) and V3A (De Yoe et al., [1996]: Proc Natl Acad Sci USA 93:2382-2386; Tootell et al., [1997]: J Neurosci 71:7060-7078) manifested both retinotopy and decreased activation to highly scrambled images. 3) The essentially nonretinotopic lateral occipital complex (LO) (Malach et al., [1995]: Proc Natl Acad Sci USA 92:8135-8139; Tootell et al., [1996]: Trends Neurosci 19:481-489) exhibited the highest sensitivity to image scrambling, and appears to be homologous to macaque the infero-temporal (IT) cortex (Tanaka [1996]: Curr Opin Neurobiol 523-529). Breaking the images into 64, 256, or 1,024 randomly scrambled blocks reduced activation in LO voxels. However, many LO voxels remained significantly activated by mildly scrambled images (16 blocks). These results suggest the existence of object-fragment representation in LO.

A descriptive study of stress management in a group of pediatric oncology nurses.

Pediatric oncology nursing is associated with highly stressful and emotional situations. This article describes and discusses major sources of occupational stress among a group of nurses participating in a stress management group. The stress sources for these nurses were preoccupation with death and dying, the professional image of the oncology nurse, the nurse as fighter in the war against disease and death, the nurses' perceived isolation from the medical staff, the nurses' perceived inferior professional status compared with that of physicians, emotional overinvolvement with patients and families, suppression of anger, and difficulties in balancing work and home demands. The following factors are suggested as major contributors to the nurses' stress and burnout: increased tendency for irrational-dysfunctional thinking styles (mainly "demandingness" and "awfulizing"), diffuse boundaries between nurses and patients, low professional self-efficacy, and wide prevalence of military metaphors.

Occupational physicians in Israel: work structure, job and personal characteristics, and job satisfaction.

This study concerns psychosocial factors among Israeli occupational physicians. Eighty-one participants (specialists, residents, and general practitioners) responded anonymously to questionnaires assessing activities demanded by the job, satisfaction from these activities, negative and positive job characteristics, job involvement, and global job satisfaction. There was little overlap between the most frequent activities (fitness for work assessments, statutory health surveillance examinations, and administrative tasks) and the activities the physicians enjoyed most (professional consultations and participation in continuing medical education (CME) activities, fitness for work assessments, and scheduled workplace visits). The most powerful predictors of job satisfaction were job involvement and satisfaction with job activities. Job involvement was related to job characteristics. The findings provide various insights for promoting job involvement and satisfaction, such as improving communication, social support, and feedback within the occupational health system and finding ways to increase quality.

Negative association between reported life events and cardiovascular disease risk factors in employed men: the CORDIS Study. Cardiovascular Occupational Risk Factors Determination in Israel.

There is evidence of a link between stressful life events and risk of cardiovascular disease, but the pathway has not been fully explored. The present study of 1859 employed men tested the association between reported intensity of life events and blood pressure and serum lipid levels, risk behaviors, and psychological distress symptoms. The findings revealed a striking disparity in the outcomes. Life events were negatively associated with systolic (p = 0.001) and diastolic (p = 0.038) blood pressure, triglycerides (p = 0.011), and uric acid (p = 0.05), even after controlling for job strain and other possible confounders. In contrast, life events were positively associated with somatic complaints (p < 0.0001), anxiety (p < 0.0001), irritability (p < 0.0001), and depression (p < 0.0001). In addition there was a linear trend between intensity level of life events and low exercise (p = 0.006), smoking (p = 0.007), and alcoholic intake (p = 0.035). The possibility that the above disparity is a product of powerful biases, such as repressive coping and negative affectivity disposition, is discussed.