American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis

The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma and Immunology Executive Committees formed the Omalizumab Joint Task Force with the purpose of reviewing the Genentech Xolair (omalizumab) clinical trials and postmarketing surveillance data on anaphylaxis and anaphylactoid reactions. Using the definition of anaphylaxis proposed at a 2005 multidisciplinary symposia, the Omalizumab Joint Task Force concluded that 35 patients had 41 episodes of anaphylaxis associated with Xolair (omalizumab) administration between June 1, 2003, and December 31, 2005. With 39,510 patients receiving Xolair (omalizumab) during the same period of time, this would correspond to an anaphylaxis-reporting rate of 0.09% of patients. Of those 36 events for which the time of reaction was known, 22 (61%) reactions occurred in the first 2 hours after one of the first 3 doses. Five (14%) of the events after the fourth or later doses occurred within 30 minutes. Considering the timing of these 36 events, an observation period of 2 hours for the first 3 injections and 30 minutes for subsequent injections would have captured 75% of the anaphylactic reactions. The OJTF report provides recommendations for physicians who prescribe Xolair (omalizumab) on (1) the suggested wait periods after administration and (2) patient education regarding anaphylaxis.     

Total hip replacement with a collarless polished cemented anatomic stem: clinical and gait analysis results at ten years follow-up

Purpose

The aim of this study was to determine outcomes of total hip replacement (THR) with the Lemania cemented femoral stem.

Methods

A total of 78 THR patients were followed and compared to 17 “fit”, healthy, elderly and 72 “frail” elderly subjects without THR, using clinical outcome measures and a portable, in-field gait analysis device at five and ten years follow-up.

Results

Forty-one patients (53 %), mean age 83.4 years, available at ten years follow-up, reported very good to excellent satisfaction. Mean Harris Hip and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were 81.2 and 10.5 points, respectively, with excellent radiological preservation of proximal femur bone stock. Spatial and temporal gait parameters were close to the fit group and better than the frail group.

Conclusions

Lemania THR demonstrated very good, stable clinical and radiological results at ten years in an older patient group, comparable to other cemented systems for primary THR. Gait analysis confirmed good walking performance in a real-life environment.     

Collateral sensitivity of resistant MRP1-overexpressing cells to flavonoids and derivatives through GSH efflux

The multidrug resistance protein 1 (MRP1) is involved in multidrug resistance of cancer cells by mediating drug efflux out of cells, often in co-transport with glutathione (GSH). GSH efflux mediated by MRP1 can be stimulated by verapamil. In cells overexpressing MRP1, we have previously shown that verapamil induced a huge intracellular GSH depletion which triggered apoptosis of the cells. That phenomenon takes place in the more global anticancer strategy called “collateral sensitivity” and could be exploited to eradicate some chemoresistant cancer cells. Seeking alternative compounds to verapamil, we screened a library of natural flavonoids and synthetic derivatives. A large number of these compounds stimulate MRP1-mediated GSH efflux and the most active ones have been evaluated for their cytotoxic effect on MRP1-overexpressing cells versus parental cells. Interestingly, some are highly and selectively cytotoxic for MRP1-cells, leading them to apoptosis. However, some others do not exhibit any cytotoxicity while promoting a strong GSH efflux, indicating that GSH efflux is necessary but not sufficient for MRP1-cells apoptosis. In support to this hypothesis, structure activity relationships show that the absence of a hydroxyl group at position 3 of the flavonoid C ring is an absolute requirement for induction of MRP1-cells death, but is not for GSH efflux stimulation. Chrysin (compound 8) and its derivatives, compounds 11 and 22, exhibit a high selectivity toward MRP1-cells with a IC₅₀ value of 4.1 μM for compound 11 and 4.9 μM for chrysin and compound 22, making them among the best described selective killer compounds of multidrug ABC transporter-overexpressing cells.     

Reduced levels of T-cell subsets CD4+ and CD8+ in homozygous sickle cell anaemia patients with splenic defects

T-lymphocyte subsets were studied in two patient groups: (1) 50 patients with homozygous sickle cell anaemia (SCA) (mean age 12 (range 3-32) years old) in good health at the time of the study who showed no infectious complication. (2) 50 patients (mean age 13 (range 4-29) years old) with normal haemoglobin rate. The global response revealed a significant increase in levels of CD3+ (P=0.04) and CD8+ (P=0.04) cells when compared with the control group, there was no significant difference in levels of CD4+ cells (P=0.05) between the two groups. However, there was a relationship between T-cell subpopulation levels and spleen status. The average values of T-cell subsets (CD4+ and CD8+) in patients with SCA-induced splenic defects (asplenic, splenomegaly or splenectomized patients) were significantly reduced when compared to SCA patients with normal spleens and the control groups. These data show that T-cell activity was reduced in patients with splenic defects. A correlation between splenic status and a perturbed host defence system in patients with SCA suggests that monitoring T-cell subsets might have prognostic value in the course of sickle cell disease.     

The Effect of an Animal-Assisted Reading Program on the Reading Rate,Accuracy and Comprehension of Grade 3 Students: A Randomized Control Study

Background

Animal-assisted therapy has been widely used with students. This study is the first known investigation into the impact of an animal-assisted reading program on reading skills, employing an experimental pre-test/post-test control group design and controlling for the effects of extra attention to student’s reading.

Objective

The purpose of the study was to evaluate the effects of an animal-assisted reading program on the reading rate, accuracy and comprehension of grade 3 students.

Method

Students identified by the ESSI Reading Test as poor readers (N = 102) were randomly assigned to three experimental groups and one control group. Twenty-seven students read to a dog in the presence of a Pets as Therapy volunteer, 24 students read directly to an adult, while 26 students read to a teddy bear in the presence of an adult. Students in the control group (n = 25) were not part of the program and continued with their normal school activities. Data collection took place before the start of the program (Time 1), directly after completion of the 10-week reading program (Time 2), and again 8 weeks after the completion of the program (Time 3).

Results

Mixed method analysis of variance revealed significant interaction between group and time on the Neale reading comprehension scores with the “dog group” scoring higher than the three other groups.

Conclusion

The animal-assisted reading program had an impact on some of the reading skills of the students who read to a dog. The program is flexible and can be applied in a variety of settings.     

Gas-phase UV absorption spectra and OH-oxidation kinetics of 1H-1,2,3-triazole and pyrazole

In this work, we report the gas phase UV absorption spectra and the kinetics of the OH-oxidation of 1H-1,2,3-triazole and pyrazole. UV spectra were determined between 200 and 250 nm, at 350 ± 2 K and at pressures between 0.09 and 0.3 Torr. The reported maximal UV absorption cross sections are (cm² per molecule): σ_{206 nm, 1H–1H-1,2,3-triazole} = 2.04 × 10⁻¹⁸ and σ_{203 nm, pyrazole} = 5.44 × 10⁻¹⁸. The very low absorption capacity of these compounds beyond 240 nm indicates that their atmospheric photodissociation is negligible. The OH-oxidation of these species was performed in an atmospheric simulation chamber coupled to an FTIR spectrometer and to a GC/MS over the temperature range 298–357 K and at atmospheric pressure. Experiments were conducted in relative mode using benzaldehyde, trans-2-hexenal and heptane as references. The obtained rate constants at 298 K were (×10⁻¹¹ cm³ per molecule per s): k(OH + 1H-1,2,3-triazole) = 2.16 ± 0.41; k(OH + pyrazole) = 2.94 ± 0.42. These results were compared to those available in the literature and discussed in terms of structure-reactivity and temperature dependency. Their tropospheric lifetimes with respect to reaction with OH radicals were then estimated.

In this work, we report the gas phase UV absorption spectra and the kinetics of the OH-oxidation of 1H-1,2,3-triazole and pyrazole.     

A Nonionic Polyethylene Oxide (PEO) Surfactant Model: Experimental and Molecular Dynamics Studies of Kolliphor EL

Polyethoxylated, nonionic surfactants are important constituents of many drug formulations, including lipid-based formulations. In an effort to better understand the behavior of formulation excipients at the molecular level, we have developed molecular dynamics (MD) models for the widely used surfactant Kolliphor EL (KOL), a triricinoleate ester of ethoxylated glycerol. In this work, we have developed models based on a single, representative molecular component modeled with 2 force field variations based on the GROMOS 53A6_DBW and 2016H66 force field parameters for polyethoxylate chains. To compare the computational models to experimental measurements, we investigated the phase behavior of KOL using nephelometry, dynamic light scattering, cross-polarized microscopy, small-angle X-ray scattering, and cryogenic transmission electron microscopy. The potential for digestion of KOL was also evaluated using an in vitro digestion experiment. We found that the size and spherical morphology of the KOL colloids at low concentrations was reproduced by the MD models as well as the growing interactions between the aggregates to from rod-like structures at high concentrations. We believe that this model reproduces the phase behavior of KOL relevant to drug absorption and that it can be used in whole formulation simulations to accelerate the formulation development.     

Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disease of motile cilia. Even though PCD is widely studied, North‐African patients have been rarely explored. In this study, we aim at confirming the clinical diagnosis and explore the genetic spectrum of PCD in a cohort of Tunisian patients. Forty clinically diagnosed patients with PCD belonging to 34 families were recruited from Tunisian pediatric departments. In each proband, targeted capture PCD panel sequencing of the 40 PCD genes was performed. PCD panel sequencing identified bi‐allelic mutations in 82% of the families in eight PCD genes. Remarkably, 23.5% of patients carried the same c.2190del CCDC39 mutation. Single nucleotide polymorphism profiling in six unrelated patients carrying this mutation has revealed a founder effect in North‐African patients. This mutation is estimated to date back at least 1,400–1,750 years ago. The identification of this major allele allowed us to suggest a cost‐effective genetic diagnostic strategy in North‐African patients with PCD.