Epicutaneous immunotherapy protects cashew-sensitized mice from anaphylaxis

Background

The prevalence of tree nut allergy has increased worldwide, and cashew has become one of the most common food allergens. More critically, cashew allergy is frequently associated with severe anaphylaxis. Despite the high medical need, no approved treatment is available and strict avoidance and preparedness for prompt treatment of allergic reactions are considered dual standard of care. In the meantime, Phase III study results suggest investigational epicutaneous immunotherapy (EPIT) may be a relevant and safe treatment for peanut allergy and may improve the quality of life for many peanut allergic children.

Objective

We aimed to evaluate the capacity of EPIT to provide protection against cashew-induced anaphylaxis in a relevant mouse model.

Methods

The efficacy of EPIT was evaluated by applying patches containing cashew allergens to cashew-sensitized mice. As negative control, sham mice received patches containing excipient. Following treatment, mice were challenged orally to cashew and anaphylactic symptoms, as well as plasmatic levels of mast-cell proteases (mMCP)-1/7, were quantified.

Results

Of 16 weeks of EPIT significantly protects against anaphylaxis by promoting a faster recovery of challenged mice. This protection was characterized by a significant reduction of temperature drop and clinical symptoms, 60 minutes after challenge. This was associated with a decrease in mast-cell reactivity as attested by the reduction of mMCP-1/7 in plasma, suggesting that EPIT specifically decrease IgE-mediated anaphylaxis.

Conclusion

We demonstrate that EPIT markedly reduced IgE-mediated allergic reactions in a mouse model of cashew allergy, which suggests that EPIT may be a relevant approach to treating cashew allergy.

     

Hereditary Cerebral Hemorrhage with Amyloidosis-Dutch Type (HCHWA-D): I - A Review of Clinical, Radiologic and Genetic Aspects

Hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D) is an autosomal dominant disease caused by deposition of β-amyloid in the leptomeningeal arteries and cortical arterioles, in addition to preamyloid deposits and amyloid plaques in the brain parenchyma.
The disease is due to a point mutation at codon 693 of the amyloid precursor protein (βPP) gene at chromosome 21. Since this point mutation is diagnostic for HCHWA-D, presymptomatic testing is feasible and offered, together with genetic counselling and psychological support, to subjects at risk. HCHWA-D is clinically characterized by recurrent strokes, in addition to dementia, which can occur after the first stroke but also preceding it. Radiological studies revealed focal lesions (hemorrhages, hemorrhagic and non-hemorrhagic infarctions) and diffuse white matter damage. Diffuse white matter hyperintensities on MRI are an early symptom of HCHWA-D since they have been found on MRI scans of subjects who had not suffered a stroke.
The presence of the diagnostic point mutation makes HCHWA-D a useful model to study the effects of cerebral amyloid angiopathy in vivo. The characteristic pathological abnormalities and its implications for Alzheimer's disease will be discussed in Part II of this article     

Monosomy 9q and trisomy 16q in a case of congenital solitary infantile myofibromatosis

Although infantile myofibromatosis (IM) is the most common fibrous proliferation of infancy, many aspects of this benign lesion have not been explored. IM histogenesis is still poorly understood, despite immunohistochemical staining and ultrastructural features that suggest a myofibroblastic origin. IM diagnosis is often made difficult by the predominance of small primitive spindle cells over myofibrobasts and the presence of intravascular growth. Genetic information is scarce, with only one karyotyped case. Here we describe a case of solitary IM discovered at birth in an otherwise healthy girl. The tumor was well circumscribed, arranged in nodules and made up of ovoid cells without atypia, in a myxoid background. Immunohistochemical evaluation indicated a myofibroblastic differentiation. The cytogenetic and fluorescence in situ hybridization analyses revealed an abnormal chromosome 9, derived from an unbalanced whole-arm translocation between chromosomes 9 and 16. On both chromosomes, the breakpoints were located in the pericentric heterochromatic region. This clonal abnormality has not been reported in other tumors and is different from the chromosome 6q deletion reported in the single previous reported IM karyotype.     

Analysis through mathematical models of the dynamics of the adrenal cortical response to ACTH in the rat

The distribution and metabolism of ACTH and the dynamics of the adrenal cortical response to this tropic hormone were characterized in the rat, through mathematical models involving data derived from experiments, where plasma corticosterone concentrations were measured following both single injections and infusions of ACTH. The models, which incorporate a previously established model of the dynamics of plasma corticosterone, were statistically validated. The simulated dynamics of the different processes linking ACTH secretion by the adenohypophysis to corticosterone secretion by the adrenal cortex include: (1) a variable MCR for plasma ACTH, modeled as the sum of a constant and a saturable degradation process; (2) the ability of the adrenal gland to secrete at a maximal rate aven after the plasma ACTH concentration has become negligible, modeled as the accumulation of an intermediary productZ directly controlled by the plasma ACTH concentration; (3) a saturable secretion with a small time constant and which, for single injections, always starts in the same fashion, modeled as a “synthesis process” whose input is a saturable function ofZ; (4) an immediate fall of the plasma corticosterone concentration at the end of the ACTH infusions, modeled as a “release process” also controlled byZ. Supported by grants from the Medical Research Council of Canada (MT-1205, MT-1555, and MA-4970), and from INSERM, France (CRL-76-5-020-4).     

Triploidy syndrome: A report on two live-born (69, XXY) and one still-born (69, XXX) infants

Two live-born cases, 69,XXY and one stillbirth, 69,XXX are reported. Further evidence is presented to delineate the triploidy syndrome. Common external and internal features which characterize the triploidy syndrome are low-set ears, hypertelorism, colobomata, syndactyly, simian creases, microphallus, undescended testes, scrotal aplasia, anomalous heart and hypoplasia of kidneys and adrenals. The triploidy syndrome encompasses features found in trisomies 13, 18 and 21. We suggest that the abnormal development of the triploidy infants is the result of the mentioned trisomies and their subsequent effect on the remaining genome.     

Stimulating effect of collagen-like peptide on the extracellular matrix of human skin: histological studies

Recent studies of our newly developed synthetic collagen-like hexapeptide have shown that it enhances cultured cell adhesion and differentiation and improves the morphology of ex vivo skin. Consequently, we were interested in further investigating the effects of the collagen-like peptide on the skin. We performed different immunostaining studies on ex vivo human skin samples treated with the collagen-like peptide at 1% in time course studies. Our research also included comparative studies with vitamin C (often used as a positive control for enhancing collagen synthesis). The results showed that application of the collagen-like peptide to the skin enhanced synthesis of many extracellular matrix (ECM) molecules and that this effect was observed very early in some ECM molecules such as laminin 5, collagen 111, and collagen IV The expression of the other molecules was increased after different times of application of the collagen-like peptide. Interestingly, comparative studies with vitamin C showed that the synthesis response of some ECM molecules such as laminin 5, collagen 111 and collagen IV was more rapid after the administration of the collagen-like peptide than through vitamin C administration. Our results also revealed that after a longer treatment period, both active ingredients stimulated ECM molecule synthesis to a similar degree, with the exception of some molecules that remained superiorafterpeptide administration, such as collagen IV and beta 1 integrin. These histological studies demonstrate the remarkable and rapid effect of the collagen-like peptide on stimulating ECM molecule synthesis and suggest wide application for the peptide in antiaging and photoaging skin care products.     

Saethre‐Chotzen syndrome: Notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation

Saethre‐Chotzen syndrome is an autosomal dominant disease characterized by craniosynostosis, ptosis, and limb and external ear abnormalities. Variable expressivity is a well‐known phenomenon in this disorder. A large Indian family has been recently identified as carrying a nonsense TWIST mutation (Q28 X) in 17 members, of whom 16 were examined in detail. Only 4 (25%) of the patients showed patent craniostenosis, namely, oxycephaly. The penetrance of craniosynostosis in this family is lower than previously reported in the literature. Fifteen patients (93%) had moderate to severe ptosis. Minor limb and external ear abnormalities were present in most patients. Eyelid features were the hallmark of the disease for 12 members of the family, suggesting that mutations in TWIST may lead to a phenotype with mainly palpebral features and no craniostenosis. The clinical analysis of this large family clearly illustrates the significant variable expressivity, probably related to haploinsufficiency because of the TWIST mutation. This phenotypic variability remains unclear but could be the result of modifier genes and/or genetic background effect, as noticed previously in the transgenic twist‐null heterozygous mice. © 2002 Wiley‐Liss, Inc.     

Prekallikrein activation in the adult respiratory distress syndrome

Prekallikrein is the zymogen form of plasma kallikrein, a proteolytic enzyme of the contact system of blood coagulation, fibrinolysis and kinin formation. To assess whether prekallikrein was activated in the adult respiratory distress syndrome (ARDS), we examined plasma samples from 12 critically ill patients including five individuals with ARDS. Using the ratio between functional prekallikrein and prekallikrein-kallikrein antigen as an index for prekallikrein activation, we found that prekallikrein was extensively activated in patients with ARDS, while this was significantly less in the case of critically ill patients without ARDS. Following activation of prekallikrein in plasma, kallikrein reacts with its substrates and with protease inhibitors, among which the alpha 2-glycoprotein C1-inhibitor. Thus, we examined whether C1-inhibitor of critically ill individuals was modified in a way suggesting that it had reacted with kallikrein. Such a modification was found in the five patients with ARDS, while it was not detectable in the seven patients without ARDS. This observation further confirmed the activation of prekallikrein in patients with ARDS. We suggest that plasma kallikrein-mediated reactions, which include bradykinin release and neutrophil activation, may contribute to the pathogenesis of ARDS.     

Hydrophobically Modified Poly(acrylic acid) Using 3‐Pentadecylcyclohexylamine: Synthesis and Rheology

Summary: Hydrophobically modified poly(acrylic acid) was synthesized using 3‐pentadecylcyclohexylamine (3‐PDCA), which was in turn synthesized from 3‐pentadecylphenol, one of the components of cashew‐nut shell liquid (CNSL), a renewable resource material. ¹H NMR spectra confirmed the incorporation of 3‐PDCA onto PAA and a series of HMPs with three different molar concentrations, viz ? 3, 5 and 7 mol‐% of 3‐PDCA, were synthesized. An increase in viscosity with increasing hydrophobic content was observed by rheological measurements. The critical association concentrations were determined using an Ubbelohde viscometer and a controlled stress rheometer. The stability of HMPs towards temperature and shear was studied. Rheological measurements showed that there was a steady increase in viscosity with increase in hydrophobe content due to the formation of reversible networks. These polymers exhibited gel‐like behavior at low concentrations (≥2 wt.‐%) with an apparent yield stress (ca. 10 Pa) and showed shear thinning properties (non‐Newtonian). However, below a critical concentration, c [η], they showed Newtonian behavior.

η_sp of unmodified and modified PAA‐Na at various polymer concentrations.