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.

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.

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.

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).

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.

Role of nuclear magnetic resonance spectroscopy (MRS) in cancer diagnosis and treatment: 31P, 23Na, and 1H MRS studies of three models of pancreatic cancer.

The role of nuclear magnetic resonance spectroscopy (MRS) in pancreatic cancer diagnosis and its treatment were assessed in three models of pancreatic neoplasms. Perfused MIA PaCa-2 human pancreatic cancer cells, s.c. implanted pancreatic tumors in hamsters, and pancreatic tumors induced in situ in rats by direct application of the carcinogen 7,12-dimethyl benzanthracene, were studied by phosphorous ((31)P), sodium ((23)Na), and proton ((1)H) MRS. (31)P spectra of pancreatic cancer were qualitatively similar to those of intact organs. There were, however, variations in peak intensities and ratios. Phosphomonoester signals were prominent in both normal pancreases and tumors, but their levels depended on the proliferation rate and on environmental conditions. Thus, the phosphomonoester:beta-nucleoside triphosphate ratio was 1.15 +/- 0.32 in 90% confluency and 1.31 +/- 0.43 in 70% confluency, and this ratio increased upon lowering the perfusion rate. Total (intra- and extracellular) sodium concentrations, measured in the solid tumors, were 39-40 micromol/g wet weight in normal pancreases. Contrary to a previous hypothesis that malignant transformation is associated with increased sodium content, our (23)Na MRS data showed that there were no significant differences between pancreatic tumors and intact organs. Proton spectra of perchloric acid extracts revealed several differences between tumors and control pancreases. The principal findings were elevated levels of the amino acid taurine, from 1.17 +/- 0.39 micromol/g wet weight in healthy pancreases, to 2.79 +/- 0.71 micromol/g wet weight in pancreatic carcinoma in rats, and lactate levels that increased from 0.92 +/- 0.2 to 6.19 +/- 1.93 micromol/g wet weight, respectively. On the other hand, creatine and glutamate were higher in the normal pancreases. Pancreatic cancer is usually resistant to chemotherapy, and we evaluated the effects of the metabolic inhibitors 2-deoxyglucose and lonidamine on the human pancreatic cancer cells by MRS and cytotoxicity studies. The IC50 of Adriamycin and 2-deoxyglucose were 1.49 +/- 0.18 x 10(6) and 136 +/- 17 microg/ml, respectively. These results were similar to data obtained previously in multidrug-resistant human breast cancer cells, which were highly resistant (33-fold) to Adriamycin but were more susceptible (9-fold) to 2-deoxyglucose than their parental cells.

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.

On the solubility of calcium deoxycholate: kinetics of precipitation and the effect of conjugated bile salts and lecithin.

In view of the low solubility of calcium deoxycholate and the possible induction of cholesterol precipitation in the gallbladder by calcium insoluble salts, we find it of interest to study the precipitation of calcium deoxycholate and its dependence on other bile components. The findings of these studies were as follows: (i) Precipitation of calcium deoxycholate from mixtures of calcium chloride and monomeric deoxycholate (at concentrations below the critical micelle concentration (CMC] is very slow even at relatively high CaCl2 concentrations (more than 20 days at 50 mM CaCl2). (ii) At higher deoxycholic acid (DOC) concentrations, precipitation of micellar DOC is faster and requires much lower calcium chloride concentrations. For any given calcium concentration, the rate of precipitation is maximal at an optimal DOC concentration. In solutions containing 150 mM NaCl, the maximal rate of precipitation occurs at about 10 mM DOC, almost independent of Ca2+ concentration. At lower ionic strength (10 mM NaCl), the optimal DOC concentration is 30 mM. These observations suggest that the most important factors in determining the rate of Ca(DOC)2 precipitation are (a) the ratio between calcium ions bound to the surface of a DOC micelle, and the [DOC] (the Ca2+/DOC binding ratio) and (b) the concentration of DOC micelles. (iii) In the presence of conjugated deoxycholates, the crystallization of calcium deoxycholate is inhibited. Phosphatidylcholine has a similar, although smaller, inhibitory effect. Upon precipitation of calcium deoxycholate from a mixed micellar system containing sodium deoxycholate, phosphatidylcholine and cholesterol, the latter two components spontaneously form vesicles. The anti-nucleating effect of PC and conjugated bile salts is explained in terms of "poisoning" of the crystallization process. In view of the latter results we conclude that under normal conditions calcium deoxycholate is not likely to precipitate in the gallbladder.

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.

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.

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.

A graduate course in work site health promotion for occupational health practitioners.

This paper describes the rationale, teaching strategies, outcomes, and a 6-month follow-up of an academic course in work site health promotion, in which 35 occupational health practitioners participated. The one-semester course was part of the Masters in Science program in occupational health at the Tel-Aviv University Medical School. The primary goals of the study were to teach the theoretical bases of work site health promotion and their application to specific health needs, and to train better role models for employees. The primary teaching strategies were: (1) facilitation of experiential learning, by encouraging students to undergo health screening and then engage in a personal health promotion plan; (2) use of health promotion experts as guest teachers; and (3) an increase in formal knowledge through formal lectures and background reading. At the time of follow-up, most of the students were still adhering to their plans and maintaining much of their health promotion achievements. Additional outcomes included increased awareness of health risks and health promotion issues, and positions as role models in the private and professional domains. The primary barrier to adherence was low frustration tolerance, which can be regarded as the major challenge to health promotion programs and courses. It is suggested that the course format is an effective means of educating health promoters.

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.

Mechanical, biochemical, and structural effects of vitamin D deficiency on the chick heart.

The effects of vitamin D deprivation on the chick heart were investigated from three aspects: cardiac contractility (+/- dP/dT), intracellular high-energy phosphorus compounds, and structural differences. Four-week-old vitamin D-deficient chicks were divided into four groups: Group A served as the normal group and received subcutaneous injections of cholecalciferol; Groups B and C were vitamin D-deficient hearts but perfused differently; Group D received daily subcutaneous injections of 5 micrograms of 1,25(OH)2D3. When the isolated spontaneously beating hearts (modified Langendorff preparation) were perfused with Krebs-Henseleit (KH) solution containing a calcium concentration of 2.5mM, the myocardial contractility of the vitamin D-deficient hearts was significantly increased when compared with group A. After the isolated heart had beaten for one hour, the myocardial contractility in the vitamin D-deficient hearts was found to decline to significantly lower values. Presacrifice administration of 1,25(OH)2D3 improved cardiac performance. Vitamin D deficiency resulted in an enhanced rate of decline of the intracellular high-energy phosphorus compounds. No differences were found in the microscopic study. These observations suggest that vitamin D has a role in cardiac function.

Burnout and risk factors for cardiovascular diseases.

The burnout syndrome denotes a constellation of physical fatigue, emotional exhaustion, and cognitive weariness resulting from chronic stress. Although it overlaps considerably with chronic fatigue as defined in internal medicine, its links with physical illness have not been systematically investigated. This exploratory study, conducted among 104 male workers free from cardiovascular disease (CVD), tested the association between burnout and two of its common concomitants--tension and listlessness--and cardiovascular risk factors. After ruling out five possible confounders (age, relative weight, smoking, alcohol use, and sports activity), the authors found that scores on burnout plus tension (tense-burnout) were associated with somatic complaints, cholesterol, glucose, triglycerides, uric acid, and, marginally, with ECG abnormalities. Workers scoring high on tense-burnout also had a significantly higher low density lipoprotein (LDL) level. Conversely, scores on burnout plus listlessness were significantly associated with glucose and negatively with diastolic blood pressure. The findings warrant further study of burnout as a predictor of cardiovascular morbidity and mortality.

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.

Developing psychosocial mindedness and sensitivity to mental health issues among primary care nurses using the Balint group method.

This study empirically evaluated the impact of a Balint group for primary care nurses on awareness of mental health and psychosocial issues and professional psychosocial efficacy. Thirteen female primary care nurses working in community clinics participated in a year-long fortnightly Balint group led by two psychologists at a regional school of nursing. Cases were presented and analyzed to highlight emotional and cognitive components and processes. Changes in professional psychosocial efficacy were assessed with the Psychological Medical Inventory (PMI). Efficacy components were (a) psychosocial abilities, (b) psychosocial sensitivity. Changes in these components and in perceived mental health topics were assessed over three time points: at initial interview, midway through group and at the end. Significant positive changes were found on both efficacy components at the final measure compared to baseline. This study indicates the beneficial effects of this method in training primary care nurses in psychosocial efficacy. It also highlights the importance of ongoing long-term training programs for mental health and psychosocial efficacy in this professional group.