Immunotoxicology studies on octoxynol-9 and nonoxynol-9 in mice

In a double-blind study, mice were injected intraperitoneally with 0.2 ml 0.2% octoxynol-9 (O-9), 0.2 ml 0.2% nonoxynol-9 (N-9), or 0.2 ml saline (control) daily for 24 days. Another control group received no treatment. All mice were immunized twice with sheep red blood cells (SRBC) and bled by caudal incision. Mice receiving N-9 lost weight (P less than 0.02), had smaller livers (P less than 0.05), and showed enlarged spleens (P less than 0.05). The N-9-treated mice did not differ from either control group in the primary or secondary anti-SRBC responses, leukocyte (WBC) counts, or in the sizes of the kidneys, hearts, lungs, or thymuses. Mice receiving O-9 showed no significant differences from either control group in any of these tests. Serum immunoglobulin M (IgM) and immunoglobulin G (IgG) levels were similar in mice treated with O-9, N-9, or saline. All 3 groups had higher levels of both classes of immunoglobulins on day 16 than did untreated controls. This study shows that O-9, given to mice in doses 3 times that used by humans, is nontoxic, whereas the same dose of N-9 has minor deleterious effects.     

Karzinomassoziierte Retinopathie (CAR) bei Mammakarzinom und Karzinoid

Fragestellung: Die Karzinomassoziierte Retinopathie (CAR) stellt ein seltenes paraneoplastisches Syndrom dar, das bislang am h?ufigsten bei kleinzelligen Bronchialkarzinomen beschrieben wurde. Wir berichten über 3 Patientinnen mit CAR in Gegenwart eines Mammakarzinoms bzw. eines Karzinoids der Cervix uteri. Patienten und Methode: Es wurden biomikroskopische, perimetrische, angiographische und elektrophysiologische Befunde erhoben. Au?erdem erfolgte eine Testung der Immunreaktivit?t der Seren an humaner Retina. Ergebnisse: Die Befunde umfa?ten ringf?rmige Gesichtsfelddefekte mit statokinetischer Dissoziation und eine pathologische St?bchen- und Zapfenantwort im ERG. Bei 1 Patientin wurde immunhistochemisch eine Reaktion im Bereich der Photorezeptorinnensegmente, der ?u?eren K?rnerschicht sowie der ?u?eren plexiformen Schicht bei fehlendem Nachweis von Antik?rpern gegen Recoverin gefunden. Diskussion: Neben dem kleinzelligen Bronchialkarzinom k?nnen auch andere Prim?rtumoren mit einer CAR vergesellschaftet sein. Der Nachweis von retinalen Autoantik?rpern unterstützt die Annahme einer tumorinduzierten Immunantwort aufgrund der Expression identischer Epitope durch die Tumorzellen. Dabei kommen offensichtlich verschiedene retinale Proteine als Autoantigene in Betracht.      

Premature failure of small-sized Shelhigh No-React porcine pulmonic valve conduit model NR-4000.

OBJECTIVE: Given the limited availability of small-sized cryopreserved pulmonary homografts, we implanted a series of Shelhigh No-React porcine pulmonic valve conduits (SPVC). The aim of this study was to evaluate the short-term performance following implantation. METHODS: From February 2000 to September 2000, the SPVC was implanted 25 times in 24 patients in the right ventricular outflow tract (RVOT) to correct congenital anomalies. The anatomical malformations were TOF/PA in eight patients, TGA/VSD/PS in four, truncus arteriosus in four, IAA/VSD/AS or AA in four, l-TGA/VSD in two and other in two. Age at operation was 2.8+/-3.9 years (mean+/-SD), including 12 patients under 1 year. The median conduit size was 14mm (range, 10-18). RESULTS: At a mean follow-up of 23+/-5 months, two late deaths (8%) have occurred. Although they were not primarily conduit related, both showed severe conduit stenosis. Twenty-one conduits (84%) showed mild to severe conduit stenosis, regurgitation or both. Two patients underwent balloon dilatation for distal conduit stenosis. Twelve conduits (48%) in 11 patients were removed at a median of 12 months (range, 2-18 months) due to RVOT obstruction in 11 and free conduit insufficiency with pseudoaneurysm in one. The typical findings of the explanted conduits were prominent intimal peel formation at the distal anastomosis without calcification. The actuarial freedom from reintervention at 18 months was 48+/-10%. CONCLUSIONS: Our experience of the SPVC with the diameter of 14mm or less has revealed a high incidence of distal conduit stenosis due to intimal peel formation resulting in early conduit failure. These findings have led us to abandon its use when other options are available.     

Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis

We report here the molecular cloning of a newly identified preprotachykinin gene, Pptc, which specifies the sequence for a new preprotachykinin protein and bioactive peptide designated hemokinin 1 (HK-1). PPT-C mRNA was detected primarily in hematopoietic cells in contrast to the previously described Ppta and Pptb genes, which are predominantly expressed in neuronal tissues. HK-1 has several biological activities that are similar to the most studied tachykinin, substance P, such as induction of plasma extravasation and mast cell degranulation. However, HK-1 also has properties that are indicative of a critical role in mouse B cell development. HK-1 stimulated the proliferation of interleukin 7-expanded B cell precursors, whereas substance P had no effect. HK-1, but not substance P, promoted the survival of freshly isolated bone marrow B lineage cells or cultured, lipopolysaccharide-stimulated pre-B cells. N-acetyl-L-trytophan-3,5-bistrifluromethyl benzyl ester, a tachykinin receptor antagonist, increased apoptosis of these cells and in vivo administration of this antagonist led to specific reductions of the B220lowCD43 population (the pre-B cell compartment) in the bone marrow and the IgMhighIgDlow population (the newly generated B cells) in the spleen. Thus, HK-1 may be an autocrine factor that is important for the survival of B cell precursors at a critical phase of development.     

Evaluation of a tiered in vitro testing strategy for assessing the ocular and dermal irritation/corrosion potential of pharmaceutical compounds for worker safety

Introduction: Irritation reactions are a frequently reported occupational illness. The potential adverse effects of pharmaceutical compounds (PCs) on eye and skin can now be assessed using validated in vitro methods.

Objectives: Our overall aim is to reduce animal testing by replacing the historically utilized in vivo test methods with validated in vitro test methods which accurately determine the ocular and dermal irritation/corrosion potential of PCs to inform worker safety within the pharmaceutical space. Bristol–Myers Squibb (BMS) and the Institute for In Vitro Sciences (IIVS) have therefore conceptualized and internally qualified a tiered in vitro testing strategy to inform occupational hazards regarding eye and skin irritation and corrosivity of PCs. For the small scale pre-qualification phase, we paired historical in vivo and newly generated in vitro data for 15 PCs to determine the predictive capacity of in vitro assays already validated for the eye and skin irritation/corrosion endpoints and accepted for certain regulatory submissions. During the post-qualification phase, a group of 24 PCs were subjected exclusively to the developed tiered testing strategy, which is based on three Organisation for Economic Co-operation and Development (OECD) in vitro methods.

Materials and methods: The qualified in vitro testing strategy utilizes the Corrositex^® assay for the corrosivity (OECD TG 435), the Bovine Corneal Opacity and Permeability (BCOP) assay for ocular irritation (OECD TG 437), and the EpiDerm? tissue model-based Skin Irritation Test (SIT) for dermal irritation (OECD TG 439). In the first step, the pH of each PC was determined. For compounds with pH extremes ≥11 or ≤2, the Corrositex^® assay was generally conducted first. For compound(s) that were incompatible with or were negative in the Corrositex^® assay or had pH values between 2 and 11, the BCOP assay and SIT were performed first.

Results: The results of the tiered testing strategy’s qualification phase demonstrated that the BCOP assay is sensitive enough to identify a wide range of eye irritation/corrosion potentials and its over-prediction rate was considered acceptable to inform occupational hazards and ensure the proper handling practices of PCs. The SIT correctly predicted the skin irritation potential of 14 out of the 15 PCs included in the qualification phase, only over-predicting one PC. In the post-qualification phase, four PCs out of four tested were predicted corrosive by the Corrositex^® assay and thus no further testing was needed or conducted. The rest of the PCs were evaluated in the BCOP assay (both neat and as a 20% dilution), with the higher response being used for hazard classification. Four PCs were determined to be severe eye irritants, 1 a moderate irritant, 8 were mild irritants, and 8 were non-irritants. The same set of PCs was evaluated using the SIT and were classified as non-irritants to skin. These results are consistent with the BMS historical in vivo results showing a very low number of PCs as skin irritants.

Conclusions: This tiered in vitro testing strategy, which replaces the use of animal studies, was found to be reasonably accurate in its predictive capacity when compared to historical in vivo results and represents a conservative and reliable platform that can be utilized for the prediction of ocular and dermal irritation/corrosion potential of PCs and for subsequent GHS classification and worker safety hazard communications.     

Matrix-Assisted Laser Desorption/Ionisation,Time-of-Flight Mass Spectrometry–Based Blood Group Genotyping—The Alternative Approach

Although matrix-assisted laser desorption/ionisation, time-of-flight mass spectrometry (MALDI-TOF MS) has previously been reported for high throughput blood group genotyping, those reports are limited to only a few blood group systems. This review describes the development of a large cooperative Swiss-German project, aiming to employ MALDI-TOF MS for the molecular detection of the blood groups Rh, Kell, Kidd, Duffy, MNSs, a comprehensive collection of low incidence antigens, as well as the platelet and granulocyte antigens HPA and HNA, representing a total of 101 blood group antigens, encoded by 170 alleles, respectively. Recent reports describe MALDI-TOF MS as a technology with short time-to-resolution, ability for high throughput, and cost-efficiency when used in genetic analysis, including forensics, pharmacogenetics, oncology and hematology. Furthermore, Kell and RhD genotyping have been performed on fetal DNA from maternal plasma with excellent results. In summary, this article introduces a new technological approach for high throughput blood group genotyping by means of MALDI-TOF MS. Although all data presented are preliminary, the observed success rates, data quality and concordance with known blood group types are highly impressive, underlining the accuracy and reliability of this cost-efficient high throughput method.     

Neurodevelopmental Outcomes in Children With Congenital Heart Disease: Evaluation and Management: A Scientific Statement From the American Heart Association

BACKGROUND: The goal of this statement was to review the available literature on surveillance, screening, evaluation, and management strategies and put forward a scientific statement that would comprehensively review the literature and create recommendations to optimize neurodevelopmental outcome in the pediatric congenital heart disease (CHD) population. METHODS AND RESULTS: A writing group appointed by the American Heart Association and American Academy of Pediatrics reviewed the available literature addressing developmental disorder and disability and developmental delay in the CHD population, with specific attention given to surveillance, screening, evaluation, and management strategies. MEDLINE and Google Scholar database searches from 1966 to 2011 were performed for English-language articles cross-referencing CHD with pertinent search terms. The reference lists of identified articles were also searched. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. A management algorithm was devised that stratified children with CHD on the basis of established risk factors. For those deemed to be at high risk for developmental disorder or disabilities or for developmental delay, formal, periodic developmental and medical evaluations are recommended. A CHD algorithm for surveillance, screening, evaluation, reevaluation, and management of developmental disorder or disability has been constructed to serve as a supplement to the 2006 American Academy of Pediatrics statement on developmental surveillance and screening. The proposed algorithm is designed to be carried out within the context of the medical home. This scientific statement is meant for medical providers within the medical home who care for patients with CHD. CONCLUSIONS: Children with CHD are at increased risk of developmental disorder or disabilities or developmental delay. Periodic developmental surveillance, screening, evaluation, and reevaluation throughout childhood may enhance identification of significant deficits, allowing for appropriate therapies and education to enhance later academic, behavioral, psychosocial, and adaptive functioning.     

Toxicological aspects of trans fat consumption over two sequential generations of rats: Oxidative damage and preference for amphetamine

Chronic consumption of processed food causes structural changes in membrane phospholipids, affecting brain neurotransmission. Here we evaluated noxious influences of dietary fats over two generations of rats on amphetamine (AMPH)-conditioned place preference (CPP). Female rats received soybean oil (SO, rich in n-6 fatty acids (FA)), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans fatty acids (TFA)) for two successive generations. Male pups from the 2nd generation were maintained on the same supplementation until 41 days of age, when they were conditioned with AMPH in CPP. While the FO group showed higher incorporation of n-3 polyunsaturated-FA (PUFA) in cortex/hippocampus, the HVF group showed TFA incorporation in these same brain areas. The SO and HVF groups showed AMPH-preference and anxiety-like symptoms during abstinence. Higher levels of protein carbonyl (PC) and lower levels of non-protein thiols (NPSH) were observed in cortex/hippocampus of the HVF group, indicating antioxidant defense system impairment. In contrast, the FO group showed no drug-preference and lower PC levels in cortex. Cortical PC was positively correlated with n-6/n-3 PUFA ratio, locomotion and anxiety-like behavior, and hippocampal PC was positively correlated with AMPH-preference, reinforcing connections between oxidative damage and AMPH-induced preference/abstinence behaviors. As brain incorporation of trans and n-6 PUFA modifies its physiological functions, it may facilitate drug addiction.