Establishment of diagnostic criteria for feline nonflea-induced hypersensitivity dermatitis

Hypersensitivity dermatitides (HD) are commonly seen in cats, and they are usually caused by environmental, food and/or flea allergens. Affected cats normally present with one of the following clinical reaction patterns: head and neck excoriations, usually symmetrical self-induced alopecia, eosinophilic skin lesions or miliary dermatitis. Importantly, none of these clinical presentations is considered to be pathognomonic for HD skin diseases, and the diagnosis of HD is usually based on the exclusion of other pruritic diseases and on a positive response to therapy. The objectives of this study were to propose sets of criteria for the diagnosis of nonflea-induced HD (NFHD). We recruited 501 cats with pruritus and skin lesions and compared clinical parameters between cats with NFHD (encompassing those with nonflea, nonfood HD and those with food HD), flea HD and other pruritic conditions. Using simulated annealing techniques, we established two sets of proposed criteria for the following two different clinical situations: (i) the diagnosis of NFHD in a population of pruritic cats; and (ii) the diagnosis of NFHD after exclusion of cats with flea HD. These criteria sets were associated with good sensitivity and specificity and may be useful for homogeneity of enrolment in clinical trials and to evaluate the probability of diagnosis of NFHD in clinical practice. Finally, these criteria were not useful to differentiate cats with NFHD from those with food HD.

Echinococcus multilocularis: the impact of ionizing radiation on metacestodes

Alveolar echinococcosis is caused by the metacestode stage of the fox tapeworm Echinococcus multilocularis. Current chemotherapeutical options for the treatment of echinococcosis are not satisfactory, and novel drugs and/or other potential means of therapy are needed. E. multilocularis metacestodes are characterized by almost potentially unlimited growth, and also display other features of cancerous tumours. In this study, we exposed metacestodes that were generated in vitro to 50-100 Gy ionizing irradiation, and subsequently investigated the short-term (10-12 days post-treatment) and long-term (14 weeks post-treatment) effects. We found, that in the short-term, no release of alkaline phosphatase (EmAP) activity as a measure for potentially induced damage and loss of viability could be detected, and that the protein expression pattern and protease activities in vesicle fluids and medium supernatants did not alter dramatically following irradiation. However, irradiation was associated with distinct morphological and ultrastructural alterations in the tissue of metacestodes, affecting most notably cell-cell contacts, mitochondrial shape, glycogen-storage cells and lipid droplet formation. These could be detected already at 10 days following treatment and remained as such also in the long-term. In addition, as determined after 14 weeks of culture, irradiation affected the proliferation and the growth of E. multilocularis metacestodes. Thus, we demonstrate that radiotherapy does not have a clear-cut parasitocidal effect, but can lead to metabolic impairment of E. multilocularis metacestodes, as reflected by the distinct morphological and structural alterations induced by irradiation treatment.

Chalcone JAI-51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors

Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to ∼20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone (p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M (p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment.

Proteomic changes in the rat brain induced by homogenous irradiation and by the bystander effect resulting from high energy synchrotron X-ray microbeams

Abstract Purpose: To further evaluate the use of microbeam irradiation (MBI) as a potential means of non-invasive brain tumor treatment by investigating the induction of a bystander effect in non-irradiated tissue. Methods: Adult rats were irradiated with 35 or 350 Gy at the European Synchotron Research Facility (ESRF), using homogenous (broad beam) irradiation (HI) or a high energy microbeam delivered to the right brain hemisphere only. The proteome of the frontal lobes were then analyzed using two-dimensional electrophoresis (2-DE) and mass spectrometry. Results: HI resulted in proteomic responses indicative of tumourigenesis; increased albumin, aconitase and triosphosphate isomerase (TPI), and decreased dihydrolipoyldehydrogenase (DLD). The MBI bystander effect proteomic changes were indicative of reactive oxygen species mediated apoptosis; reduced TPI, prohibitin and tubulin and increased glial fibrillary acidic protein (GFAP). These potentially anti-tumourigenic apoptotic proteomic changes are also associated with neurodegeneration. However the bystander effect also increased heat shock protein (HSP) 71 turnover. HSP 71 is known to protect against all of the neurological disorders characterized by the bystander effect proteome changes. Conclusions: These results indicate that the collective interaction of these MBI-induced bystander effect proteins and their mediation by HSP 71, may confer a protective effect which now warrants additional experimental attention.

Injuries, sequelae, and treatment of lightning-induced injuries: 10 years of experience at a swiss trauma center

Principals. Lightning is one of the most powerful and spectacular natural phenomena. Lightning strikes to humans are uncommon but can cause devastating injuries. We analyzed lightning-related admissions to our emergency department from January 2000 to December 2010 to review and highlight the main features of lightning-related injuries. Methods. All data were collected prospectively and entered in the emergency department' database (Qualicare Switzerland) and retrospectively analyzed. Results. Nine patients with lightning-related injuries presented to our emergency department. Four were female, and five were male. The most common site of injury was the nervous system (6 out of 9 patients) followed by the cardiovascular system (5 out of 9 patients). The third most common injuries occurred to the skin (3 out of 9 patients). Four of the patients had to be hospitalized for further observation. Conclusion. Reports of lightning strikes and related injuries are scarce. The establishment of an international register would therefore benefit the understanding of their injury patterns and facilitate specific treatment.

The role of olfactory cues in the sequential radiation of a gall-boring beetle

Species diversity itself may cause additional species diversity. According to recent findings, some species modify their environment in such a way that they facilitate the creation of new niches for other species to evolve to fill. Given the vast speciesdiversity of insects, the occurrence of such sequential radiation of species is likely common among herbivorous insects and the species that depend on them, many of them being insects as well. Herbivorous insects often have close associations with specific host plants and their preferences for mating and ovipositing on a specific host-plant species can reproductively isolate host-specific populations, facilitating speciation. Previous research by our laboratory has established that there are two distinct populations of thegall fly, Eurosta solidaginis (Tephritidae), which attack different species of goldenrods, Solidago altissima (Asteraceae) and S. gigantea. The gall fly’s host-associated differentiation is facilitating the divergence and potential speciation of twosubpopulations of the gall-boring beetle Mordellistena convicta (Mordellidae) by providing new resources (galls on stems of the galdenrods) for the gall-boring beetles. These beetles exist as two host-plant associated populations of inquilines that inhabit the galls induced by the gall fly. While our previous research has provided genetic and behavioral evidence for host-race formation, little is known about the role of their host plants in assortative mating and oviposition-site selection of the gall-boring beetles’ hostassociated populations. Volatile emissions from host plants can play a major role in assisting herbivores to locate their natal host plants and thus facilitate assortative mating and host-specific oviposition. The present study investigated the role of host-plant volatiles in host fidelity (mating on the host plant) and oviposition preference of M. convicta by measuring its behavioral responses to the host-plant volatile emissions using Y-tube olfactometers. In total, we tested behavioral responses of 615 beetles. Our resultsshow that M. convicta adults are attracted to their natal host galls (67% of S. altissima-emerging beetles and 70% of S. gigantea-emerging beetles) and avoid the alternate host galls (75% of S. altissima-emerging beetles and 66% of S. gigantea-emerging beetles),while showing no preference for, or avoidance of, ungalled plants from either species. This suggests that the gall beetles can orient to the volatile chemicals emitted by the galls and can potentially use them to identify suitable sites for mating and/or oviposition. Thus, host-associated mating and oviposition may play a role in the sequential speciation of the gall-boring beetle.

A Computational Analysis of the Collision-Induced Dissociation Mechanisms of the Dipeptide Glycine-Serine Under Mass Spectrometry

Collision-induced dissociation (CID) of peptides using tandem mass spectrometry (MS) has been used to determine the identity of peptides and other large biological molecules. Mass spectrometry (MS) is a useful tool for determining the identity of molecules based on their interaction with electromagnetic fields. If coupled with another method like infrared (IR) vibrational spectroscopy, MS can provide structural information, but in its own right, MS can only provide the mass-to-charge (m/z) ratio of the fragments produced, which may not be enough information to determine the mechanism of the collision-induced dissociation (CID) of the molecule. In this case, theoretical calculations provide a useful companion for MS data and yield clues about the energetics of the dissociation. In this study, negative ion electrospray tandem MS was used to study the CID of the deprotonated dipeptide glycine-serine (Gly-Ser). Though negative ion MS is not as popular a choice as positive ion MS, studies by Bowie et al. show that it yields unique clues about molecular structure which complement positive ion spectroscopy, such as characteristic fragmentations like the loss of formaldehyde from the serine residue.2 The increase in the collision energy in the mass spectrometer alters the flexibility of the dipeptide backbone, enabling isomerizations (reactions not resulting in a fragment loss) and dissociations to take place. The mechanism of the CID of Gly-Ser was studied using two computational methods, B3LYP/6-311+G* and M06-2X/6-311++G**. The main pathway for molecular dissociation was analyzed in 5 conformers in an attempt to verify the initial mechanism proposed by Dr. James Swan after examination of the MS data. The results suggest that the loss of formaldehyde from serine, which Bowie et al. indicates is a characteristic of the presence of serine in a protein residue, is an endothermic reaction that is made possible by the conversion of the translational energy of the ion into internal energy as the ion collides with the inert collision gas. It has also been determined that the M06-2X functional¿s improved description of medium and long-range correlation makes it more effective than the B3LYP functional at finding elusive transition states. M06-2X also more accurately predicts the energy of those transition states than does B3LYP. A second CID mechanism, which passes through intermediates with the same m/z ratio as the main pathway for molecular dissociation, but different structures, including a diketopiperazine intermediate, was also studied. This pathway for molecular dissociation was analyzed with 3 conformers and the M06-2X functional, due to its previously determined effectiveness. The results suggest that the latter pathway, which meets the same intermediate masses as the first mechanism, is lower in overall energy and therefore a more likely pathway of dissociation than the first mechanism.

Etiology and pathogenesis of adverse drug reactions

In clinical routine, adverse drug reactions (ADR) are common, and they should be included in the differential diagnosis in all patients undergoing drug treatment. Only part of those ADR are immune-mediated hypersensitivity reactions and thus true drug allergies. Far more common are non-immune-mediated ADR, e.g. due to the pharmacological properties of the drug or to the individual predisposition of the patient (enzymopathies, cytokine dysbalance, mast cell hyperreactivity). In true drug allergiesT cell- and immunoglobulin E (lgE)-mediated reactions dominate the clinical presentation. T cell-mediated ADR usually have a delayed appearance and include skin eruptions in most cases. Nevertheless, it should not be forgotten that they may involve systemic T cell activation and thus take a severe, sometimes lethal turn. Clinical danger signs are involvement of mucosal surfaces, blistering within the exanthematous skin areas and systemic symptoms, e.g. fever or malaise. Drug presentation via antigen-presenting cells to T cells can either involve the classical pathway of haptenization of endogenous proteins or be directly mediated via noncovalent binding to immune receptors (MHC molecules or T cell receptors), the so-called p-i concept. Flare-up reactions during the acute phase of T cell-mediated ADR should not be mistaken for true drug allergies, as they only occur in the setting of a highly activated T cell pool. IgE-mediated ADR are less frequent and involve mast cells and/or basophils as peripheral effector cells. Recent data suggest that certain patients with drug allergy have a preexistent sensitization although they have never been exposed to the culprit drug, probably due to cross-reactivity. Thus, allergic drug reactions on first encounter are possible. In general, the extent of cross-reactivity is higher in IgE-compared to T cell-mediated ADR. Based on a specific ethnic background and only for severe T cell-mediated ADR to certain drugs, a strong HLA association has been established recently.

Io volcano observer (IVO) integrated approach to optimizing system design for radiation challenges

One of the major challenges for a mission to the Jovian system is the radiation tolerance of the spacecraft (S/C) and the payload. Moreover, being able to achieve science observations with high signal to noise ratios (SNR), while passing through the high flux radiation zones, requires additional ingenuity on the part of the instrument provider. Consequently, the radiation mitigation is closely intertwined with the payload, spacecraft and trajectory design, and requires a systems-level approach. This paper presents a design for the Io Volcano Observer (IVO), a Discovery mission concept that makes multiple close encounters with Io while orbiting Jupiter. The mission aims to answer key outstanding questions about Io, especially the nature of its intense active volcanism and the internal processes that drive it. The payload includes narrow-angle and wide-angle cameras (NAC and WAC), dual fluxgate magnetometers (FGM), a thermal mapper (ThM), dual ion and neutral mass spectrometers (INMS), and dual plasma ion analyzers (PIA). The radiation mitigation is implemented by drawing upon experiences from designs and studies for missions such as the Radiation Belt Storm Probes (RBSP) and Jupiter Europa Orbiter (JEO). At the core of the radiation mitigation is IVO's inclined and highly elliptical orbit, which leads to rapid passes through the most intense radiation near Io, minimizing the total ionizing dose (177 krads behind 100 mils of Aluminum with radiation design margin (RDM) of 2 after 7 encounters). The payload and the spacecraft are designed specifically to accommodate the fast flyby velocities (e.g. the spacecraft is radioisotope powered, remaining small and agile without any flexible appendages). The science instruments, which collect the majority of the high-priority data when close to Io and thus near the peak flux, also have to mitigate transient noise in their detectors. The cameras use a combination of shielding and CMOS detectors with extremely fast readout to mi- imize noise. INMS microchannel plate detectors and PIA channel electron multipliers require additional shielding. The FGM is not sensitive to noise induced by energetic particles and the ThM microbolometer detector is nearly insensitive. Detailed SNR calculations are presented. To facilitate targeting agility, all of the spacecraft components are shielded separately since this approach is more mass efficient than using a radiation vault. IVO uses proven radiation-hardened parts (rated at 100 krad behind equivalent shielding of 280 mils of Aluminum with RDM of 2) and is expected to have ample mass margin to increase shielding if needed.

Grover's disease induced by cetuximab

A 71-year-old man exhibited an acute acneiform rash affecting the face and the upper trunk about 2 weeks after starting cetuximab, an epidermal growth factor (EGF) receptor antagonist treatment for metastatic colon cancer. The skin eruption faded after stopping cetuximab and applying topical corticosteroids. The reexposure to cetuximab 3 weeks later provoked a more extended relapse of the skin rash, which then clinically and histologically corresponded to transient acantholytic dermatosis . While the acneiform cutaneous side effects of the EGF receptor antagonists are interpreted as a result of the direct interference with pilosebaceous follicle homeostasis, in this case an acrosyringium-related pathogenesis might be postulated. Applying topical corticosteroids and emollients, the cetuximab therapy could be pursued.

Role of endogenous Fas (CD95/Apo-1) ligand in balloon-induced apoptosis, inflammation, and neointima formation

BACKGROUND: Fas (CD95/Apo-1) ligand (FasL)-induced apoptosis in Fas-bearing cells is critically involved in modulating immune reactions and tissue repair. Apoptosis has also been described after mechanical vascular injury such as percutaneous coronary intervention. However, the relevance of cell death in this context of vascular repair remains unknown. METHODS AND RESULTS: To determine whether FasL-induced apoptosis is causally related to neointimal lesion formation, we subjected FasL-deficient (generalized lymphoproliferative disorder [gld], C57BL/6J) and corresponding wild-type (WT) mice to carotid balloon distension injury, which induces marked endothelial denudation and medial cell death. FasL expression in WT mice was induced in injured vessels compared with untreated arteries (P<0.05; n=5). Conversely, absence of functional FasL in gld mice decreased medial and intimal apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling [TUNEL] index) at 1 hour and 7 days after balloon injury (P<0.05; n=6). In addition, peritoneal macrophages isolated from gld mice showed no apoptosis and enhanced migration (P<0.05; n=4). In parallel, we observed increased balloon-induced macrophage infiltrations (anti-CD68) in injured arteries of FasL-deficient animals (P<0.05; n=6). Together with enhanced proliferation (bromodeoxyuridine index; P<0.05), these events resulted in a further increase in medial and neointimal cells (P<0.01; n=8) with thickened neointima in gld mice (intima/media ratio, x3.8 of WT; P<0.01). CONCLUSIONS: Our data identify proapoptotic and antiinflammatory effects of endogenous FasL as important factors in the process of neointimal lesion formation after balloon injury. Moreover, they suggest that activation of FasL may decrease neointimal thickening after percutaneous coronary intervention.

[Radiation exposure in (90)Y-Zevalin therapy: results of a prospective multicentre trial]

AIM of this study was the assessment of the radiation exposure from preparation and application of (90)Y-Zevalin, the measurement of the dose rate at the patient, the exposure of family members as well as the determination of the activity concentration in urine of patients. METHODS: Overall data from 31 therapeutic administrations carried out in four institutions were evaluated. During preparation and application of (90)Y-Zevalin the finger exposures of radiochemists, technicians, and physicians were measured. The dose rate of the patient was measured immediately after radioimmunotherapy. In patients treated in a nuclear medicine therapy unit, urine was collected over a two day period and the corresponding activity was determined. Family members of outpatients were asked to wear a dosimeter over a seven day period. RESULTS: During the preparation we found a maximum skin dose of 6 mSv at the average, and during application of 3 mSv, respectively. After administration of (90)Y the dose rate was 0.4 +/- 0.1 microSv/h at 2 m distance. Urine measurements yielded a cumulated 24 h excretion of 3.9 +/- 1.4% and 4.4 +/- 1.4% within 48 h, respectively, that is equivalent to 43 +/- 18 and 50 +/- 20 MBq of (90)Y, respectively. Family members received a radiation exposure of 40 +/- 14 microSv over seven days. CONCLUSION: During preparation and application of (90)Y-Zevalin appropriate radiation shielding is necessary. For family members as well as nursing staff no additional special radiation protection measures beyond those being common for other nuclear medicine procedures are necessary.

Skin rejuvenation without a scalpel. I. Fillers

Fillers are an important tool in the armamentarium of the physician combating aging phenomena. A wide variety of filler substances are now available that meet many, but by far not all, needs in aesthetic medicine. The most commonly used substances now are hyaluronic acid and collagen preparations that have slightly different indications, but collagen requires pre-use testing to rule out inflammatory complications. Poly-L-lactic acid has gained its place in the filling of adipose tissue wasting in HIV-infected patients. Autologous fat is easy to harvest and inject and has virtually no risk of adverse side effects. Permanent fillers may be of advantage but carry the risk of permanent adverse reactions. Skillful combination of different fillers as well as with botulinum toxin injections and other cosmetic procedures may give optimal results.

Anxiety trait modulates psychophysiological reactions, but not habituation processes related to affective auditory stimuli

BACKGROUND: It is well known that there are specific peripheral activation patterns associated with the emotional valence of sounds. However, it is unclear how these effects adapt over time. The personality traits influencing these processes are also not clear. Anxiety disorders influence the autonomic activation related to emotional processing. However, personality anxiety traits have never been studied in the context of affective auditory stimuli. METHODS: Heart rate, skin conductance, zygomatic muscle activity and subjective rating of emotional valence and arousal were recorded in healthy subjects during the presentation of pleasant, unpleasant, and neutral sounds. Recordings were repeated 1 week later to examine possible time-dependent changes related to habituation and sensitization processes. RESULTS AND CONCLUSION: There was not a generalized habituation or sensitization process related to the repeated presentation of affective sounds, but rather, specific adaptation processes for each physiological measure. These observations are consistent with previous studies performed with affective pictures and simple tones. Thus, the measures of skin conductance activity showed the strongest changes over time, including habituation during the first presentation session and sensitization at the end of the second presentation session, whereas the facial electromyographic activity habituated only for the neutral stimuli and the heart rate did not habituate at all. Finally, we showed that the measure of personality trait anxiety influenced the orienting reaction to affective sounds, but not the adaptation processes related to the repeated presentation of these sounds.

[Influence of local anaesthesia on pain and distress induced by bloodless castration methods in young lambs]

Behavioural and cortisol responses of lambs were used as indicators of pain and distress to assess short- and long-term effects of bloodless castration methods with and without local anaesthesia. Eighty lambs, aged 2-7 days, were control handled or castrated by crushing- Burdizzo- or rubber ring method with and without local anaesthesia. Either 4 mg/kg diluted lidocaine, or corresponding volumes of physiologic sodium chloride solution were distributed in both spermatic cords and the scrotal neck. The serum cortisol response was monitored for 48 h, behavioural- and clinical traits over a 3-month period. The crushing castration method was excluded from the study after 10 lambs had been castrated, since this method showed severe local reactions. Local anaesthesia significantly reduced behavioural and cortisol responses after rubber ring castration and tendentially after Burdizzo castration. Prolonged or chronic pain after rubber ring castration with anaesthesia was not evident. If combined with local anaesthesia, both the rubber ring and the Burdizzo method are acceptable methods for castration of lambs up to one week of age.