General considerations on rapid desensitization for drug hypersensitivity - a consensus statement

Drug hypersensitivity reactions can occur with most drugs, are unpredictable, may affect any organ or system, and range widely in clinical severity from mild pruritus to anaphylaxis. In most cases, the suspected drug is avoided in the future. However, for certain patients, the particular drug may be essential for optimal therapy. Under these circumstances, desensitization may be performed. Drug desensitization is defined as the induction of a temporary state of tolerance of a compound responsible for a hypersensitivity reaction. It is performed by administering increasing doses of the medication concerned over a short period of time (from several hours to a few days) until the total cumulative therapeutic dose is achieved and tolerated. It is a high-risk procedure used only in patients in whom alternatives are less effective or not available after a positive risk/benefit analysis. Desensitization protocols have been developed and are used in patients with allergic reactions to antibiotics (mainly penicillin), insulins, sulfonamides, chemotherapeutic and biologic agents, and many other drugs. Desensitization is mainly performed in IgE-mediated reactions, but also in reactions where drug-specific IgE have not been demonstrated. Desensitization induces a temporary tolerant state, which can only be maintained by continuous administration of the medication. Thus, for treatments like chemotherapy, which have an average interval of 4 weeks between cycles, the procedure must be repeated for every new course. In this paper, some background information on rapid desensitization procedures is provided. We define the drugs and drug reactions indicated for such procedures, describe the possible mechanism of action, and discuss the indications and contraindications. The data should serve as background information for a database (accessible via the EAACI-homepage) with standardized protocols for rapid desensitization for antibiotics, chemotherapeutic agents, monoclonal antibodies/fusion proteins, and other drugs.

Overjet correction and space closure mechanisms for Class II treatment by extracting the maxillary first molars

To analyze the mechanism of overjet correction and space closure when treating Class II Division 1 patients by extracting the maxillary first molars.

Exercise induces rapid interstitial lung water accumulation in patients with chronic mountain sickness

Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world. In its more advanced stages, exercise intolerance is often found, but the underlying mechanism is not known. Recent evidence indicates that exercise-induced pulmonary hypertension is markedly exaggerated in CMS. We speculated that this problem may cause pulmonary fluid accumulation and aggravate hypoxemia during exercise.

Rapid downregulation of innate immune cells, interleukin-12 and interleukin-23 in generalized pustular psoriasis with infliximab in combination with acitretin

Generalized pustular psoriasis (GPP) is a severe inflammatory disease characterized by recurrent eruptions of sterile pustules on erythematous skin. Although tumor necrosis factor (TNF) antagonists may lead to a rapid resolution of GPP, the mechanism of action of these agents remains to be investigated. Here, we sought to evaluate markers of immune response in the skin of a patient who experienced a rapid amelioration of GPP after treatment with infliximab and acitretin.

Quantification of plasma carnitine and acylcarnitines by high-performance liquid chromatography-tandem mass spectrometry using online solid-phase extraction

Carnitine is an amino acid derivative that plays a key role in energy metabolism. Endogenous carnitine is found in its free form or esterified with acyl groups of several chain lengths. Quantification of carnitine and acylcarnitines is of particular interest for screening for research and metabolic disorders. We developed a method with online solid-phase extraction coupled to high-performance liquid chromatography and tandem mass spectrometry to quantify carnitine and three acylcarnitines with different polarity (acetylcarnitine, octanoylcarnitine, and palmitoylcarnitine). Plasma samples were deproteinized with methanol, loaded on a cation exchange trapping column and separated on a reversed-phase C8 column using heptafluorobutyric acid as an ion-pairing reagent. Considering the endogenous nature of the analytes, we quantified with the standard addition method and with external deuterated standards. Solid-phase extraction and separation were achieved within 8 min. Recoveries of carnitine and acylcarnitines were between 98 and 105 %. Both quantification methods were equally accurate (all values within 84 to 116 % of target concentrations) and precise (day-to-day variation of less than 18 %) for all carnitine species and concentrations analyzed. The method was used successfully for determination of carnitine and acylcarnitines in different human samples. In conclusion, we present a method for simultaneous quantification of carnitine and acylcarnitines with a rapid sample work-up. This approach requires small sample volumes and a short analysis time, and it can be applied for the determination of other acylcarnitines than the acylcarnitines tested. The method is useful for applications in research and clinical routine.

Endothelial function and sleep: associations of flow-mediated dilation with perceived sleep quality and rapid eye movement (REM) sleep.

Endothelial function typically precedes clinical manifestations of cardiovascular disease and provides a potential mechanism for the associations observed between cardiovascular disease and sleep quality. This study examined how subjective and objective indicators of sleep quality relate to endothelial function, as measured by brachial artery flow-mediated dilation (FMD). In a clinical research centre, 100 non-shift working adults (mean age: 36 years) completed FMD testing and the Pittsburgh Sleep Quality Index, along with a polysomnography assessment to obtain the following measures: slow wave sleep, percentage rapid eye movement (REM) sleep, REM sleep latency, total arousal index, total sleep time, wake after sleep onset, sleep efficiency and apnea-hypopnea index. Bivariate correlations and follow-up multiple regressions examined how FMD related to subjective (i.e., Pittsburgh Sleep Quality Index scores) and objective (i.e., polysomnography-derived) indicators of sleep quality. After FMD showed bivariate correlations with Pittsburgh Sleep Quality Index scores, percentage REM sleep and REM latency, further examination with separate regression models indicated that these associations remained significant after adjustments for sex, age, race, hypertension, body mass index, apnea-hypopnea index, smoking and income (Ps < 0.05). Specifically, as FMD decreased, scores on the Pittsburgh Sleep Quality Index increased (indicating decreased subjective sleep quality) and percentage REM sleep decreased, while REM sleep latency increased (Ps < 0.05). Poorer subjective sleep quality and adverse changes in REM sleep were associated with diminished vasodilation, which could link sleep disturbances to cardiovascular disease.

Revisiting the Nd-142 deficits in the 1.48 Ga Khariar alkaline rocks, India

The 146Sm–142Nd system plays a central role in tracing the silicate differentiation of the Earth prior to 4.1 Ga. After this time, given its initial abundance, the 146Sm can be considered to be extinct. Upadhyay et al. (2009) reported unexpected negative 142Nd anomalies in 1.48 Ga rocks of the Khariar nepheline syenite complex (India) and inferred that an early enriched, low-Sm/Nd reservoir must have contributed to the mantle source rocks of the Khariar complex. As 146Sm had been effectively extinct for about 2.6 billion years before the crystallisation of the Khariar samples, this Nd signature should have remained isolated from the convective mantle for at least that long. It was thus suggested that the source rock of Khariar samples had been sequestered in the lithospheric root of the Indian craton. Using a different chemical separation method, and a different Thermal Ionization Mass Spectrometry (TIMS) analysis protocol, the present study attempted to replicate these negative 142Nd anomalies, but none were found. To determine which data set is correct, we investigated three possible sources of bias between them: imperfect cancellation of Faraday collector efficiencies during multidynamic TIMS analysis, rapid sample fractionation between the sequential measurement of 146Nd/144Nd and 142Nd/144Nd, and non-exponential law behaviour resulting from so-called “domain mixing.” Incomplete cancellation of collector efficiencies was found unlikely to cause resolvable biases at the estimated level of variation among collector efficiencies. Even in the case of highly variable efficiency and resolvable biases, there is no reason to suspect that they would reproducibly affect only four rocks out of 10 analysed by Upadhyay et al. (2009). Although domain mixing may explain apparent “reverse” fractionation trends observed in some TIMS analyses, it cannot be the cause of the apparent negative anomalies in the study of Upadhyay et al. (2009). It was determined that rapid mass fractionation during the course of a multidynamic TIMS analysis can bias all measured Nd ratios. After applying an approximate correction for this effect, only one rock from Upadhyay et al. (2009) retained an apparent negative 142Nd anomaly. This, in conjunction with our new, anomaly-free data set measured at fractionation rates too low to cause bias, leads to the conclusion that the anomalies reported by Upadhyay et al. (2009) are a subtle and reproducible analytical artefact. The absence of negative 142Nd anomalies in these rocks relaxes the need for a mechanism (other than crust formation) that can isolate a Nd reservoir from the convective mantle for billions of years.

Development of a method for fast and automatic radiocarbon measurement of aerosol samples by online coupling of an elemental analyzer with a MICADAS AMS

A fast and automatic method for radiocarbon analysis of aerosol samples is presented. This type of analysis requires high number of sample measurements of low carbon masses, but accepts precisions lower than for carbon dating analysis. The method is based on online Trapping CO2 and coupling an elemental analyzer with a MICADAS AMS by means of a gas interface. It gives similar results to a previously validated reference method for the same set of samples. This method is fast and automatic and typically provides uncertainties of 1.5–5% for representative aerosol samples. It proves to be robust and reliable and allows for overnight and unattended measurements. A constant and cross contamination correction is included, which indicates a constant contamination of 1.4 ± 0.2 μg C with 70 ± 7 pMC and a cross contamination of (0.2 ± 0.1)% from the previous sample. A Real-time online coupling version of the method was also investigated. It shows promising results for standard materials with slightly higher uncertainties than the Trapping online approach.

Online Reputation Systems and Cumulative Advantage

The study of online reputation systems and their importance for promoting trust and cooperation and, therefore, the smooth functioning of online markets has received considerable attention over the last few years. In the first part of our talk we will try to give a brief overview of the existing theoretical and empirical work in this field, summarize the main findings from this research and identify open questions where results are either controversial or do not yet exist. The second part of our talk will focus on one of these issues that deserve further research, namely the relation between online reputation systems and processes of "cumulative advantage." Cumulative advantage is the mechanism where a favorable relative position of having a good reputation becomes a resource for further relative gains. The process leads to increased status inequality and a heavily skewed distribution of number of feedbacks, i.e. the ties in the reputation network. We present empirical evidence for direct and indirect reputation effects on the micro level of an auction reputation system and discuss the distributional consequences for the market level.