The Cole relaxation frequency as a parameter to identify cancer in breast tissue.

PURPOSE: To correlate the Cole relaxation frequencies obtained from measurements of the electrical properties of breast tissue to the presence or absence of cancer. METHODS: Four-lead impedance measurements were obtained on ex vivo specimens extracted during surgery from 187 volunteer patients. Data were acquired with a commercial Solartron impedance bridge employing 4-lead Ag-AgCl or blackened platinum (BPt) electrodes at frequencies logarithmically spaced from 1 Hz to 3.2 × 10(7) Hz utilizing 6-10 frequencies per decade. The Cole frequencies obtained from these measurements were correlated with the tissue health status (cancer or noncancer) obtained from histological analysis of the specimens. RESULTS: Analysis of the impedance measurements showed that the Cole relaxation frequencies correlated to the presence or absence of cancer in the examined tissue with a sensitivity up to 100% (95% CI, 99%-100%) and a specificity up to 85% (95% CI, 79%-91%) based on the ROC curve of the data with the Cole frequency as the classifier. CONCLUSIONS: The results show that the Cole frequency alone is a viable classifier for malignant breast anomalies. Results of the current work are consistent with recent bioimpedance measurements on single cell and cell suspension breast cell lines.

An educational multimedia campaign improves stroke knowledge and risk perception in different stroke risk groups.

BACKGROUND AND PURPOSE: Stroke risk factor knowledge and individual risk perception are low in the general public. Our study aimed at identifying the educational effects of a multimedia campaign on stroke knowledge and risk perception in several subgroups at increased risk of stroke. METHODS: Telephone surveys were administered in a random sample of 500 members of the general public, before and immediately after an intense 3 months educational campaign using various mass and print media. RESULTS: A total of 32.7% of respondents considered themselves as being at risk of stroke before, and 41.9% (P < 0.01) after the intervention. Evaluation of stroke risk increased with number of appreciated individual stroke risk factors. Knowledge of different stroke risks varied considerably and proved to be especially high in obese individuals (98.7%) and smokers (97.9%) and particularly low in patients with coronary heart disease (80.6%). CONCLUSIONS: Our data indicate that educational programs and the introduction of stroke risk factors can increase stroke risk perception in the public. Even though some risk groups (smokers, obese) reveal a ceiling effect, future campaigns should focus on high risk populations remarkably underrating their risk, like those with coronary heart disease or the elderly.

Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis.

HFE-related hereditary haemochromatosis (HH) is an iron overload disease attributed to the highly prevalent homozygosity for the C282Y mutation in the HFE gene. The pathophysiology of this error in iron metabolism is not completely elucidated yet, although deficiency of the iron regulatory hormone hepcidin appears to play a role. Ways of diagnosing iron overload include measurement of the serum iron parameters, i.e. serum transferrin saturation and serum ferritin, by a liver biopsy or by calculating the amount of mobilisable body iron withdrawn by phlebotomies. Clinical signs attributed to HFE-related HH include liver failure, arthralgia, chronic fatigue, diabetes mellitus and congestive heart failure. organ failure can be prevented by phlebotomies starting before irreversible damage has occurred. Therefore, screening to facilitate early diagnosis is desirable in individuals at risk of developing HFE-related iron overload. over time it appeared that the clinical penetrance of the HFE mutations was much lower than had previously been thought. This changed the opinion about a suitable screening modality from case detection, via population screening, to family screening as the most appropriate method to prevent HFE-related disease. However, before the implementation of family screening it is vital to have thorough information on the relevance of the specific health problem involved, on the clinical penetrance of C282Y homozygosity and on the effectiveness of the screening approach.

Morbidity and mortality in first-degree relatives of C282Y homozygous probands with clinically detected haemochromatosis compared with the general population: the HEmochromatosis FAmily Study (HEFAS).

BACKGROUND: Family screening has been suggested as a sophisticated model for the early detection of HFE-related hereditary haemochromatosis (HH). However, until now, controlled studies on the morbidity and mortality in families with HH are lacking. METHODS: Data on iron parameters, morbidity and mortality were collected from 224 dutch C282Y-homozygous probands with clinically overt HH and 735 of their first-degree family members, all participating in the HEmochromatosis fAmily study (HEfAs). These data were compared with results obtained from an age- and gender-matched normal population. HEfAs and controls filled in similar questionnaires on demographics, lifestyle factors, health, morbidity and mortality. RESULTS: A significantly higher proportion of the HEfAs first-degree family members reported to be diagnosed with haemochromatosis-related diseases: 45.7 vs 19.4% of the matched normal population (McNemar p<0.001). Mortality among siblings, children and parents in the HEFAS population was similar to that in the relatives of matched control. CONCLUSION: In this study we show that, morbidity among first-degree family members of C282Y-homozygous probands previously diagnosed with clinically proven HH is higher than that in an age- and gender-matched normal population. Further studies are needed to definitely connect these increase morbidity figures to increase prevalenc of the C282Y mutated HFE-gene and elevated serum iron indices.

Correction of electrode polarization contributions to the dielectric properties of normal and cancerous breast tissues at audio/radiofrequencies.

Spurious contributions from electrode polarization (EP) are a major nuisance in dielectric measurements of biological tissues and hamper accurate determination of tissue properties in the audio/radiofrequencies. Various electrode geometries and/or treatments have been employed traditionally to reduce EP contributions, although none succeeded to completely remove EP from measurements on tissues for all practical frequency ranges. A method of correction for contributions of EP to the dielectric properties of tissues is proposed. The method is based on modeling the electrode impedance with suitable functions and on the observation that certain parameters are only dependent on electrodes properties and can thus be determined separately. The method is tested on various samples with known properties, and its usefulness is demonstrated with samples of normal and cancerous human female breast tissue. It is observed that the dielectric properties of the tissues over the frequency range 40 Hz-100 MHz are significantly different among different types of breast tissue. This observation is used further to demonstrate that, by scanning the tip of the measuring dielectric probe (with modest spatial resolution) across a sample of excised breast tissue, significant variations in the electrical properties are detected at a position where a tumor is located. This study shows that dielectric spectroscopy has the potential to offer a viable alternative to the current methods for detection of breast cancer in vivo.

[Hereditary haemochromatosis: novel genes, novel diseases and hepcidin]. / Hereditaire hemochromatose: nieuwe genen, nieuwe ziekten en hepcidine.

Since the discovery of the HFE gene of hereditary haemochromatosis in 1996 several new genetic defects have been identified, enabling explanation of the cause and variety of this disease. To date, at least 5 major types of hereditary haemochromatosis have been recognised. All these genes encode for proteins that are involved in metabolic pathways relevant to hepcidin synthesis in the liver. Hepcidin is a small protein that regulates the activity of the iron exporting protein ferroportin in the basolateral membrane of duodenal cells and the cell membrane of macrophages and thereby controls serum iron concentration. Plasma hepcidin concentration is elevated in body iron excess and by inflammatory stimuli, and is lowered in erythroid iron demand, hypoxia and most types of hereditary haemochromatosis. It is the clinician's task to diagnose hereditary haemochromatosis before irreversible tissue damage arises and at the same time to differentiate between ongoing iron accumulation and increasingly prevalent disorders with elevated serum ferritin such as the metabolic syndrome.

Iron absorption during epoetin alfa therapy for chemotherapy-associated anaemia.

Absorption of a physiological dose of ferrous iron was studied in 18 patients with solid malignancy receiving epoetin therapy for mild chemotherapy-associated anemia. The historical control group consisted of 25 iron replete volunteers (iron absorption 20 +/- 11% in males and 26 +/- 13% in females) and 21 patients with uncomplicated iron deficiency (iron absorption 71 +/- 19%). Iron absorption was increased in the majority of the cancer patients (iron absorption 59 +/- 35%). There were no significant differences in iron absorption between cancer patients who were iron replete or iron deficient according to current clinical practice guidelines (iron deficiency: transferrin saturation < 20% and/or serum ferritin < 100 ng/mL). Red cell iron incorporation was not disturbed in the majority (89%) of patients.

HFE mutations and risk of coronary heart disease in middle-aged women.

BACKGROUND: Although heterozygosity for the C282Y mutation in the HFE gene has been associated with an increased risk of cardiovascular events, epidemiological studies remain inconclusive. The aim of the present study was to obtain further evidence as to whether HFE mutations are associated with risk of coronary heart disease (CHD) in middle-aged women. We used data of a cohort of 15 236 Dutch middle-aged women to investigate whether C282Y carriers and H63D carriers are at increased risk of coronary heart disease compared with non-carriers. MATERIALS AND METHODS: Women were included in the study between 1993 and 1997 and were followed until 1 January 2000 for cardiovascular events. HFE genotyping was performed on all 211 coronary heart disease cases and a randomly selected sample from the baseline cohort (n = 1526). A weighted Cox proportional hazards model was used to estimate crude, age-adjusted and multivariate adjusted hazard ratios for C282Y and H63D carriership in relation to coronary heart disease. RESULTS: Compared with non-carriers, those that carried the C282Y allele were not at increased risk for CHD (HR = 1.25, 95% CI = 0.74-2.09). Neither did we find an association between the H63D mutation and CHD risk (HR = 0.73, 95% CI = 0.43-1.24). CONCLUSIONS: Our results are in accordance with similar studies to date, for which we present a meta-analysis. HFE mutations appear not to affect the risk of coronary heart disease.

Iron enhances endothelial cell activation in response to Cytomegalovirus or Chlamydia pneumoniae infection.

BACKGROUND: Chronic inflammation has been implemented in the pathogenesis of inflammatory diseases like atherosclerosis. Several pathogens like Chlamydia pneumoniae (Cp) and cytomegalovirus (CMV) result in inflammation and thereby are potentially artherogenic. Those infections could trigger endothelial activation, the starting point of the atherogenic inflammatory cascade. Considering the role of iron in a wide range of infection processes, the presence of iron may complicate infection-mediated endothelial activation. MATERIALS AND METHODS: Endothelial intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelial selectin (E-selectin) expression were measured using flow cytometry, as an indication of endothelial activation. Cytotoxicity was monitored using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Immunostaining was applied to measure Cp and CMV infectivity to endothelial cells. RESULTS: An increased number of infected endothelial cells in a monolayer population leads to a raised expression of adhesion molecules of the whole cell population, suggesting paracrine interactions. Iron additively up-regulated Cp-induced VCAM-1 expression, whereas synergistically potentiated Cp-induced ICAM-1 expression. Together with CMV, iron also enhanced ICAM-1 and VCAM-1 expression. These iron effects were observed without modulation of the initial infectivity of both microorganisms. Moreover, the effects of iron could be reversed by intracellular iron chelation or radical scavenging, conforming modulating effects of iron on endothelial activation after infections. CONCLUSIONS: Endothelial response towards chronic infections depends on intracellular iron levels. Iron status in populations positive for Cp or CMV infections should be considered as a potential determinant for the development of atherosclerosis.

Partial purification and characterization of ferritin from the liver and intestinal mucosa of chickens, turtledoves and mynahs.

Ferritin is the iron-storage protein responsible for sequestering excess iron, to be stored in a safe way in the liver or to be shed with the intestinal epithelial cells. The properties of ferritin in iron-overload-susceptible birds have not been elucidated. Furthermore, there is only scarce information on mucosal ferritin, with no information at all in avian species. Here we have studied the liver and proximal intestine ferritins of iron-overload-susceptible (Indian hill mynahs, common mynahs) and non-susceptible (turtledoves, chicken) bird species. A brief purification process preceded native polyacrylamide gel electrophoresis and staining the gels for protein and iron. Protein amounts and iron-binding characteristics of ferritin were measured and ferritin saturation levels were calculated. Although ferritin protein amounts did not differ significantly, liver and mucosal ferritins of sensitive bird species incorporated much more iron, leading to high saturation levels. Significantly higher ferritin iron content and saturation were observed in the liver of both mynah species and in the intestinal ferritin of Indian hill mynahs when compared with the non-susceptible species. Ferritin appears not to play a major role in the regulation of iron absorption, implicating other phases in iron transport to be more important in the onset and process of iron overload in birds.

A topodiagnostic investigation on body lateropulsion in medullary infarcts.

Body lateropulsion may occur without signs of vestibular dysfunction and vestibular nucleus involvement. The authors examined 10 such patients with three-dimensional brainstem mapping. Body lateropulsion without limb ataxia reflected an impairment of vestibulospinal postural control caused by a lesion of the descending lateral vestibulospinal tract, whereas body lateropulsion with limb ataxia was probably the consequence of impaired or absent proprioceptive information caused by a lesion of the ascending dorsal spino-cerebellar tract.

[Horner's syndrome -- update on neuroanatomy, topographic diagnosis and etiology]. / Das Horner-Syndrom -- Ein Update zur Neuroanatomie, topographischen Differenzialdiagnostik und Atiologie.

Due to the complex neuroanatomy of the sympatho-excitatory pathway, Horner's syndrome represents a clinical sign that may result from a variety of lesions in the central and peripheral nervous system. The purpose of the present communication is to help the reader to localize the site of the lesion and to demonstrate the most common etiologic mechanisms resulting in Horner's syndrome. The functional anatomy of the sympathetic supply to the iris, eyelids, facial sweat glands and blood vessels is reviewed and in particular the structure of the central pathway updated. Moreover, pharmacological testing and tests of sudomotor function are described that may help to guide the decision regarding useful additional diagnostic, especially neuroimaging procedures. Finally, a schematic overview is given on the most common pathology, considering additional clinical signs and symptoms.

Brainstem reflex circuits revisited.

Our current understanding of brainstem reflex physiology comes chiefly from the classic anatomical-functional correlation studies that traced the central circuits underlying brainstem reflexes and establishing reflex abnormalities as markers for specific areas of lesion. These studies nevertheless had the disadvantage of deriving from post-mortem findings in only a few patients. We developed a voxel-based model of the human brainstem designed to import and normalize MRIs, select groups of patients with or without a given dysfunction, compare their MRIs statistically, and construct three-plane maps showing the statistical probability of lesion. Using this method, we studied 180 patients with focal brainstem infarction. All subjects underwent a dedicated MRI study of the brainstem and the whole series of brainstem tests currently used in clinical neurophysiology: early (R1) and late (R2) blink reflex, early (SP1) and late (SP2) masseter inhibitory reflex, and the jaw jerk to chin tapping. Significance levels were highest for R1, SP1 and R2 afferent abnormalities. Patients with abnormalities in all three reflexes had lesions involving the primary sensory neurons in the ventral pons, before the afferents directed to the respective reflex circuits diverge. Patients with an isolated abnormality of R1 and SP1 responses had lesions that involved the ipsilateral dorsal pons, near the fourth ventricle floor, and lay close to each other. The area with the highest probabilities of lesion for the R2-afferent abnormality was in the ipsilateral dorsal-lateral medulla at the inferior olive level. SP2 abnormalities reached a low level of significance, in the same region as R2. Only few patients had a crossed-type abnormality of SP1, SP2 or R2; that of SP1 reached significance in the median pontine tegmentum rostral to the main trigeminal nucleus. Although abnormal in 38 patients, the jaw jerk appeared to have no cluster location. Because our voxel-based model quantitatively compares lesions in patients with or without a given reflex abnormality, it minimizes the risk that the significant areas depict vascular territories rather than common spots within the territory housing the reflex circuit. By analysing statistical data for a large cohort of patients, it also identifies the most frequent lesion location for each response. The finding of multireflex abnormalities reflects damage of the primary afferent neurons; hence it provides no evidence of an intra-axial lesion. The jaw jerk, perhaps the brainstem reflex most widely used in clinical neurophysiology, had no apparent topodiagnostic value, probably because it depends strongly on peripheral variables, including dental occlusion.

[Diffusion-weighted MRT in vertebrobasilar ischemia. Application, sensitivity, and prognostic value]. / Diffusionsgewichtetes MRT bei vertebrobasilären Ischämien. Anwendung, Sensitivität und prognostischer Wert.

The aim of this study was to evaluate the applicability, sensitivity, and predictive power of diffusion-weighted MR imaging (DWI) in the diagnosis of vertebrobasilar infarction. From 1997 to 2002, we prospectively recruited 268 patients with acute signs and symptoms suspective of vertebrobasilar ischemia. The patients underwent biplanar EPI-T2 and EPI DWI within 24 h after onset of symptoms and high-resolution MRI as a control within 7 days. One hundred twenty-one patients had additional CT scanning. The DWI revealed acute vertebrobasilar infarction in 71.0%. The mean time exposure of DWI was 8 min and thus no more than that of CT imaging. It showed significantly more acute lesions than CT imaging (28.0%), but additional high-resolution MRI was not able to reveal more lesions than DWI alone. Even in 42 patients with reversible brainstem or cerebellar symptoms classified as TIA or PRIND, DWI demonstrated acute ischemia in 42.8%. Sixty-three patients with optimal final diagnosis of vertebrobasilar ischemia had normal DWI. One week after onset of symptoms, 88.9% of these patients had recovered completely or showed minimal symptoms. Therefore, DWI is a sensitive indicator of acute vertebrobasilar ischemia. It is no more time-consuming than CT imaging, and normal DWI is a predictor of good clinical outcome in patients with brainstem or cerebellar infarction.

Topodiagnostic investigations on the sympathoexcitatory brain stem pathway using a new method of three dimensional brain stem mapping.

OBJECTIVES: To study the incompletely understood sympathoexcitatory pathway through the human brain stem, using a new method of three dimensional brain stem mapping on the basis of digitally postprocessed magnetic resonance imaging (MRI). METHODS: 258 consecutive patients presenting with acute signs of brain stem ischaemia underwent biplane T2 and EPI diffusion weighted MRI, with slice orientation parallel and perpendicular to a transversal slice selection of the stereotactic anatomical atlas of Schaltenbrand and Wahren, 1977. The individual slices were digitally normalised and projected onto the appropriate slices of the anatomical atlas. For correlation analysis lesions were imported into a three dimensional model of the human brain stem. RESULTS: 31 of the 258 patients had Horner's syndrome caused by acute brain stem ischaemia. Only four of the patients with Horner's syndrome had pontine infarctions, 12 had pontomedullary lesions, and 15 had medullary lesions. Correlation analysis showed significantly affected voxels in the dorsolateral medulla but not in the pons. A statistical comparison with infarct topology in patients with medullary lesions but without Horner's syndrome indicated that involvement of the medial and ventral part of affected voxels located in the ventrolateral medullary tegmentum was specific for Horner's syndrome. CONCLUSIONS: Based on this first in vivo topodiagnostic study, the central sympathoexcitatory pathway probably descends through the dorsal pons before converging on specific generators in the ventrolateral medullary tegmentum at a level below the IX and X nerve exits.

Iron metabolism in mynah birds (Gracula religiosa) resembles human hereditary haemochromatosis.

Iron overload is a very frequent finding in several animal species and a genetic predisposition is suggested. In one of the most commonly reported species with susceptibility for iron overload (mynah bird), it was recently shown that the cause of this pathophysiology is high uptake and retention of dietary iron. Here we compare susceptible (mynahs) with non-susceptible avian species (chickens) by evaluating iron uptake at the intestinal absorptive cell level. Enterocytes from mynahs and chickens were isolated and uptake of Fe(II) and Fe(III) was studied in vitro. It was found that Fe(III) uptake is much lower than Fe(II) uptake for both species. Although liver iron, present only in hepatocytes, was at least 10-fold higher in mynahs than chickens, enterocyte Fe(II) uptake was considerably higher in mynahs. Fe(II) uptake showed saturation at the studied concentrations in both species. Kinetic studies revealed a three-fold increase in Vmax for mynahs. Calculated values for the uptake kinetics of the probable membrane transporter suggest that mynah bird enterocytes have a significantly higher limiting uptake rate, due to the possible increase in the number of transporters when compared with chicken enterocytes. The susceptibility of this species is due to intestinal iron uptake despite hepatic iron accumulation, implicating a 'mis-sensing' of body iron similarly to human hereditary haemochromatosis.

Iron and infection: competition between host and microbes for a precious element.

During infection microbes attack host tissues, causing damage to specific organs, sepsis or even death. For proliferation microbes desperately need iron for which they have to compete with the host. Micro-organisms have developed an abundant number of strategies to acquire iron from their specific environment and to transport the element to sites of incorporation into biologically important molecules. As part of the non-specific defence mechanisms against infection, the body modifies iron metabolism in order to make iron less available for micro-organisms. Such processes have a profound effect on the immune system and are also expressed in other forms of inflammation. Microbial iron transport systems are explored as targets for antibiotic treatment and vaccines. In particular, iron chelators, used for the treatment of iron overload may become important drugs for fighting bacterial and viral infections.

Diffusion weighted magnetic resonance imaging in the diagnosis of reversible ischaemic deficits of the brainstem.

OBJECTIVES: To evaluate the sensitivity of diffusion weighted magnetic resonance imaging (MRI) for the diagnosis of clinically suspected reversible ischaemic deficits of the brainstem. METHODS: A total of 158 consecutive patients presenting with acute signs of brainstem dysfunction were investigated using EPI diffusion weighted MRI within 24 hours of the onset of symptoms. High resolution T1 and T2 weighted imaging was performed as a follow up after a median of six days. RESULTS: Fourteen of the 158 patients had a complete clinical recovery within 24 hours (transitory ischaemic attack (TIA)), and 19 patients recovered in less than one week (prolonged reversible neurological deficit (RIND)). Diffusion weighted MRI showed acute ischaemic deficits in 39% of patients with transient neurological deficits. The detection rate seemed to be higher in patients with longer lasting symptoms, but the difference between patients with TIA (29%) and RIND (47%) was not significant. CONCLUSIONS: Diffusion weighted MRI is a sensitive indicator of acute ischaemic brainstem deficits even in patients with reversible neurological deficit. Early identification of patients with TIA and increased risk of stroke may influence acute management and improve patient outcome.