Ingrid Böhm

Biological applications of magnetic nanoparticles.

In this review an overview about biological applications of magnetic colloidal nanoparticles will be given, which comprises their synthesis, characterization, and in vitro and in vivo applications. The potential future role of magnetic nanoparticles compared to other functional nanoparticles will be discussed by highlighting the possibility of integration with other nanostructures and with existing biotechnology as well as by pointing out the specific properties of magnetic colloids. Current limitations in the fabrication process and issues related with the outcome of the particles in the body will be also pointed out in order to address the remaining challenges for an extended application of magnetic nanoparticles in medicine.

Myths and misconceptions concerning contrast media-induced anaphylaxis: a narrative review

ABSTRACT Contrast-enhanced radiological examinations are an increasingly important diagnostic tool in modern medicine. All approved and available contrast media (iodinated and gadolinium-based) are safe compounds that are well-tolerated by most patients. However, a small percentage of patients exhibit contrast medium-induced adverse drug reactions that are dose-dependent and predictable (type A) or an even smaller cohort experience so-called type B (dose-independent, non-predictable). To increase patients‘ safety, recommendations/guidelines have been put forth in the literature and advice passed down informally by radiologists in practice to ensure contrast media safety. Through these, both reasonable suggestions as well as misinterpretations and myths (such as the misleading terms “allergy-like” reactions, and “iodine-allergy”, the wrong assumption that the initial contact to a contrast medium could not induce an allergy, the estimation that an anti-allergy premedication could suppress all possible adverse reactions, and interleukin-2 as a risk/trigger for contrast medium adverse events) have arisen. Since the latter are not only unhelpful but also potentially reduce patients’ safety, such myths and misconceptions are the focus of this review.

Classification of acute and delayed contrast media-induced reactions: proposal of a three-step system.

Physicians and scientists use a broad spectrum of terms to classify contrast media (CM)-induced adverse reactions. In particular, the designation of hypersensitivity reactions is quite varied. Consequently, comparisons of different papers dealing with this subject are difficult or even impossible. Moreover, general descriptions may lead to problems in understanding reactions in patients with a history of adverse CM-reactions, and in efficiently managing these patients. Therefore, the goal of this paper is to suggest an easy system to clearly classify these reactions. The proposed three-step systems (3SS) is built up as follows: step 1 exactly describes the clinical features, including their severity; step 2 categorizes the time point of the onset (immediate or nonimmediate); and step 3 generally classifies the reaction (hypersensitivity or nonhypersensitivity reaction). The 3SS may facilitate better understanding of the clinical manifestations of adverse CM reactions and may support the prevention of these reactions on the basis of personalized medicine approaches.

Magnetic Resonance Cell-Tracking Studies: Spectrophotometry-Based Method for the Quantification of Cellular Iron Content after Loading with Superparamagnetic Iron Oxide Nanoparticles

The purpose of this article is to present a user-friendly tool for quantifying the iron content of superparamagnetic labeled cells before cell tracking by magnetic resonance imaging (MRI). Iron quantification was evaluated by using Prussian blue staining and spectrophotometry. White blood cells were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Labeling was confirmed by light microscopy. Subsequently, the cells were embedded in a phantom and scanned on a 3 T magnetic resonance tomography (MRT) whole-body system. Mean peak wavelengths Λpeak was determined at A720nm (range 719–722 nm). Linearity was proven for the measuring range 0.5 to 10 μg Fe/mL (r = .9958; p = 2.2 × 10−12). The limit of detection was 0.01 μg Fe/mL (0.1785 mM), and the limit of quantification was 0.04 μg Fe/mL (0.714 mM). Accuracy was demonstrated by comparison with atomic absorption spectrometry. Precision and robustness were also proven. On T2-weighted images, signal intensity varied according to the iron concentration of SPIO-labeled cells. Absorption spectrophotometry is both a highly sensitive and user-friendly technique that is feasible for quantifying the iron content of magnetically labeled cells. The presented data suggest that spectrophotometry is a promising tool for promoting the implementation of magnetic resonance-based cell tracking in routine clinical applications (from bench to bedside).

Contrast Agents and Ionization with Respect to Safety for Patients and Doctors

In hemodialysis patients, radiographic imaging with iodinated contrast medium (ICM) application plays a central role in the diagnosis and/or follow-up of disease-related conditions. Therefore, safety aspects concerning ICM administration and radiation exposure have a great impact on this group of patients. Current hardware and software improvements including the design and synthesis of modern contrast compounds allow the use of very small amounts of ICM in concert with low radiation exposure. Undesirable ICM side effects are divided into type A (predictable reactions such as heat feeling, headache, and contrast-induced acute kidney injury, for example) and type B (nonpredictable or hypersensitivity) reactions; this chapter deals with the latter. The first onset cannot be prevented. To prevent hypersensitivity upon reexposure of ICM, an allergological workup is recommended. If this is not possible and ICM is necessary, the patient should receive a premedication (H1 antihistamine with or without corticosteroids). Current imaging hardware and software improvements (e.g. such as additional filtration of the X-ray beam) allow the use of very small amount of ICM and small X-ray doses. Proper communication among the team involved in the treatment of a patient may allow to apply imaging protocols and efficient imaging strategies limiting radiation exposure to a minimum. Practical recommendations will guide the reader how to use radiation and ICM efficiently to improve both patient and staff safety.

Contrast Medium-Induced Leukopenia

dependent of the application route (e.g. intracavitary, intravenous) and of the osmolality of the ICM molecule [1, 2] . Third, the mechanism that lead to both severe transient leukopenia and a slight decrease in leukocyte numbers is currently unclear. Although the authors called it a special form of anaphylaxis, this seems rather unlikely to me because the patient lacked characteristic symptoms of anaphylaxis (e.g. urticaria, angio-edema, shortness of breath, drop of blood pressure) [1] . Moreover, in a patient with clinical anaphylaxis the leukocytes remained unchanged [3] . Since ICMs are not cytotoxic, other mechanisms such as cell destruction by complement activation [4] and/or apoptosis [5] should be discussed as responsible for the observed leukopenia. Taken together, the article presented by Kovoor and Morgan [1] is of great impact because, for the first time, it shows that leukopenia is an adverse CM-induced reaction. This article should encourage other physicians/scientists to regularly analyze the leukocyte counts in patients undergoing ICM-enhanced examinations. Although the mechanism of the observed severe transient leukopenia is currently unclear, it will become evident when this topic receives attention in the medical community. I would like to commend Kovoor and Morgan [1] for their excellent work regarding an unusual adverse reaction induced by an iodinated contrast medium (ICM). For the first time, they reported on severe transient leukopenia induced by the ICM conray 280 that had been applied for hysterosalpingography [1] . First, the fact that the paper by Kovoor and Morgan highlights the absolute number of leukocytes after ICM injection is of very great impact, and therefore the article is a mile stone in ICM safety research. Although determination of the number of peripheral leukocytes is very easy to perform, currently little is known concerning the influence of ICM injection on this parameter. Only few papers [2] have been published so far that show the effects of ICM on leukocyte counts. Interestingly, the injection of non-ionic ICM lead to decreasing leukocyte numbers [2] . Although none of the patients acquired leukopenia, and the changes were statistically not significant, this clinical observation confirmed the findings of Kovoor and Morgan [1] . It seems likely that in most patients receiving ICM, the leukocyte counts drop slightly, and in certain individuals severe transient leukopenia occurs. Second, the ability to transiently decrease leukocyte numbers seems to be inReceived. February 15, 2010 Accepted: Febuary 20, 2010 Published online: June 16, 2010

Latex allergy in patients suspected for contrast medium hypersensitivity: A neglected differential diagnosis

Sir, Anaphylaxis is a rare but potential acute and lifethreatening adverse reaction after contrast medium (CM) injection. In some cases, a “ hidden ” allergen may be responsible that is primarily not apparent. Latex is present in different medical devices (e.g. gloves, catheters), and could be such a “ hidden ” allergen. Although a broad range of papers show latex as an important allergen that is responsible for a signifi cant proportion of anaphylactic reactions during surgical and other medical procedures (1 – 3), in the context of CM-enhanced radiological procedures it has rarely been investigated or even mentioned (4 – 9). Therefore, the purpose of this letter is to point out latex as a possible cause of hypersensitivity reactions in patients suspected for CM reactions. Latex is now probably the second most important cause of intraoperative anaphylaxis (1). Other agents such as colloids, opioids, and radiographic contrast material account for less than 10% of all reactions (1). But a subtle search did not reveal a paper presenting latex allergy as cause of anaphylaxis during an interventional radiological procedure. Only one review article mentions latex allergy as a potential cause in anaphylactic reactions after administration of anesthetics and/or CM (5). Therefore, knowledge concerning latex allergy as a differential diagnosis in CM hypersensitivity is sparse. Currently, in concert with CM injection, some aspects such as interleukin-2 treatment (10) are overestimated, while other risks like latex hypersensitivity are largely neglected. Clinical symptoms of latex allergy comprise contact urticaria, generalized urticaria and/or pruritus, dermatitis, allergic rhinitis, conjunctivitis, asthma, angioedema, and anaphylaxis. Therefore, it is indistinguishable fρom symptoms induced by CM. One case report presents a 65-year-old man with pulmonary artery catheter monitoring who acquired a hypersensitivity reaction after bypass surgery (7). Latex allergy was suspected because the reaction started before any exposure to iodinated CM (7). The pulmonary artery catheter was inserted and within 2 min the patient developed anaphylaxis and ventricular fi brillation. It became evident that the pulmonary artery catheter used had a latex balloon and that the patient had a latex sensitization with allergen-specifi c IgE. In a similar case with latex allergy anaphylaxis occurred immediately

Pretesting With the Injection of Small Doses of Contrast Media Is Dangerous and Should Be Omitted.

With great interest I read the article by Soffer et al published in the January issue of Vascular and Endovascular Surgery. The authors clearly point to the need for a predicting test in patients with a positive history of an adverse reactions against contrast media, but unfortunately they chose the wrong way. Pretesting by using intravenous injection of small doses of contrast media to possibly predict a reactivity is a very old fashioned method that has been abandoned many years ago because it has no clinical value and is harmful. Interestingly, while useful medical knowledge sometimes falls into oblivion, wrong facts are carried on the heritage. Skin testing can be done with either the skin prick test or the intradermal test. By using the first option, only a very low amount of the contrast medium reaches the skin mast cells that induces in most tested patients a negative reaction and only a very small proportion of patients (with very severe clinical reactions) acquires a positive test result. Therefore, skin prick test is no useful procedure to obtain a valuable test result. As stated previously, for immediate reactors, the intradermal tests are the most sensitive, whereas delayed intradermal tests in combination with patch tests are needed for optimal sensitivity in nonimmediate or delayed reactions. The intradermal test should be done with escalating concentrations of the contrast media: for example, starting with a 10 2 dilution, followed by a 10 1 dilution, and finally by the intradermal injection of the undiluted contrast medium. If the patient shows a positive test result, the testing of the next concentration step should be not performed. Such a test procedure is safe and well tolerated by the patients and can be recommended as diagnostic tool both to verify the culprit contrast medium and to possible identify alternate nonculprit compounds. A pretesting by using a small dose of a contrast medium has been inaugurated in the 1940s by Jungmichel, for example. Afterward several radiologists pretested patients at risk. The evaluation of the results of the pretesting was disappointing: Pretesting has been shown to be of no clinical value, serious reactions and even deaths occurred despite negative pretesting results, and deaths and serious reactions were induced by the pretesting itself. Therefore, pretesting was given up. For several decades, pretesting was not performed. But with the introduction of the abovementioned skin tests, the pretesting or challenging (with or without escalating test does of the contrast medium) was reintroduced. Acquisition of a sensitization has not yet been investigated, it should be the same as mentioned above. Taken together, currently, intradermal testing up to undiluted contrast medium concentrations is the method of the choice both to verify the culprit contrast medium and to possibly find nonculprit contrast media that could be injected as safe alternate compounds. Pretesting with small volumes of the contrast medium (with or without premedication) is dangerous because it bears the risk of the acquisition of a sensitization; this means that even in negatively tested patients, reactions of all grades of severity could be possible. Therefore, pretesting with small intravenously injected doses of the contrast medium should be abandoned.

Enhancing patient value efficiently: Medical history interviews create patient satisfaction and contribute to an improved quality of radiologic examinations

Diagnostic radiology examinations are generally very efficient processes optimized for high throughput and for serving the needs of physicians. On the downside, streamlined examinations disrupt the personal relationship between diagnosticians and patients. The radiology associations RSNA and ACR consider low visibility of radiologists a threat to the profession. Therefore, they launched counter-acting initiatives that aim at increasing patient satisfaction by providing more personal attention and care, and by raising knowledge about the discipline. However, they did not formulate concrete instructions on how to integrate care by radiologists into the examination process while inhibiting the flow minimally. From an internal patient satisfaction survey, we have seen that patients rated satisfaction with care and attention by physicians relatively low, indicating that patients would welcome a possibility to communicate with radiologists. In a controlled experimental setting, we have then changed our process to include a short medical history interview. Thereby we could corroborate that lack of educated communication is the primary cause of diminished satisfaction and could establish that the duration of the encounter is not critical to achieving improvement. Importantly, the interview also helped to improve the quality of the examination. Thus, short medical history interviews are a very efficient way to increase value by maximizing patient satisfaction and examination quality. Our approach is easy to implement in other radiology clinics that are interested in becoming more patient-centered and in raising patient satisfaction.

Monitoring of tumor burden in vivo by optical imaging in a xenograft SCID mouse model: evaluation of two fluorescent proteins of the GFP-superfamily.

Background Mouse models of human-malignant-melanoma (MM) are important tools to study tumor dynamics. The enhanced green fluorescent protein (EGFP) is widely used in molecular imaging approaches, together with optical scanners, and fluorescence imaging. Purpose Currently, there are no data available as to whether other fluorescent proteins are more suitable. The goal of this preclinical study was to analyze two fluorescent proteins of the GFP superfamily under real-time in vivo conditions using fluorescence reflectance imaging (FRI). Material and Methods The human melanoma cell line MeWo was stable transfected with one plasmid: pEGFP-C1 or pDsRed1-N1. We investigated two severe combined immunodeficiency (SCID)-mice groups: A (solid xenografts) and B (xenografts as metastases). After three weeks, the animals were weekly imaged by FRI. Afterwards the mice were euthanized and metastases were imaged in situ: to quantify the cutis-dependent reduction of emitted light, we compared signal intensities obtained by metastases in vivo with signal intensities obtained by in situ liver parenchyma preparations. Results More than 90% of cells were stable transfected. EGFP-/DsRed-xenograft tumors had identical growth kinetics. In vivo the emitted light by DsRed tumors/metastases was much brighter than by EGFP. DsRed metastases were earlier (3 vs. 5 weeks) and much more sensitive detectable than EGFP metastases. Cutis-dependent reduction of emitted light was greater in EGFP than in DsRed mice (tenfold). Autofluorescence of DsRed was lower than of EGFP. Conclusion We established an in vivo xenograft mouse model (DsRed-MeWo) that is reliable, reproducible, and superior to the EGFP model as a preclinical tool to study innovative therapies by FRI under real-time in vivo conditions.