Treatment of naturally occurring asthma with inhaled fluticasone or oral prednisolone: A randomized pilot trial.

The objective of this study was to compare inhaled glucocorticoids with oral glucocorticoids for treatment of naturally occurring feline asthma. Secondary goals were to evaluate serum allergy testing results in cats and to quantify the effect of an inhaled glucocorticoid (fluticasone) on glucose homeostasis. Nine cats with asthma were enrolled on the basis of clinical signs, thoracic radiographic findings, and airway eosinophilia. Cats were randomized and 4 cats were treated with oral glucocorticoids and 5 cats with inhaled glucocorticoids, with a 7-day course of oral glucocorticoids overlapping at the start of therapy. Cats were evaluated at baseline and at 8 wk with thoracic radiographs, bronchoalveolar lavage, lung function testing, and fructosamine levels. Serum allergen panels were evaluated. All cats were clinically normal after treatment and had significantly improved airway eosinophilia and decreased nucleated cell count. No improvement was seen in radiographic changes after treatment with either therapy. Oral, but not inhaled glucocorticoids, caused a decrease in airway resistance, although cats in the inhaled group had a higher baseline resistance than those in the oral group. Fructosamine levels did not change with treatment. Fifty percent of cats tested positive for immunoglobulin E (IgE) antibodies. Asthma is a heterogeneous condition; individual cats responded well to both oral and inhaled glucocorticoids. Ongoing evaluation of the potential underlying causes and therapeutic options is warranted with a larger group of cats.

L'objectif de l'étude était de comparer le traitement de l'asthme félin avec des glucocorticoïdes inhalés et administrés par voie entérale. Les objectifs secondaires étaient d'évaluer les résultats de tests d'allergies de chats atteints d'asthme félin et de quantifier l'effet d'un glucocorticoïde inhalé (fluticasone) sur l'homéostasie du glucose. Neuf chats atteints d'asthme félin ont été recrutés selon les signes cliniques, les trouvailles radiographiques et les évaluations cytologiques des voies aériennes (éosinophilie). Les chats ont été randomisés. Quatre chats ont été traités avec des glucocorticoïdes par voie entérale et cinq chats avec des glucocorticoïdes inhalés dont les 7 premiers jours ont été associés à l'administration de glucocorticoïdes par voie orale. Les chats ont initialement été évalués au moment du recrutement et puis à huit semaines avec des radiographies thoraciques, lavage bronchoalvéolaire, tests de fonction pulmonaire et dosage de la fructosamine. Des tests sériques d'allergènes ont également été évalués. Tous les chats ont eu une résolution des signes cliniques après le traitement et avaient une amélioration significative du compte éosinophilique du LBA. Aucune amélioration des lésions radiographiques suivant le traitement soit inhalé ou entéral n'a été observée. Seuls les glucocorticoïdes entéraux ont causés une diminution de la résistance des voies respiratoires. Toutefois les chats du groupe de traitement de glucocorticoïdes inhalés avaient, avant l'initiation du traitement, une résistance pulmonaire plus importante. Les niveaux de fructosamine n'ont pas changé significativement, et ce dans les deux groupes de traitement. 50 % des chats ont testé positif pour des anticorps IgE contre des allergènes inhalés communs. L'asthme est une entité clinique hétérogène; les chats ont individuellement bien répondu autant au traitement inhalé qu'au traitement entéral. L'étude des potentielles causes sous-jacente et des différentes options thérapeutiques sont recommandées dans une population plus grande de chats.(Traduit par les auteurs).

Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans.

Gastrointestinal nematodes (GINs) of humans, e.g., hookworms, negatively impact childhood growth, cognition, nutrition, educational attainment, income, productivity, and pregnancy. Hundreds of millions of people are targeted with mass drug administration (MDA) of donated benzimidazole anthelmintics. However, benzimidazole efficacy against GINs is suboptimal, and reduced/low efficacy has been seen. Developing an anthelmintic for human MDA is daunting: it must be safe, effective, inexpensive, stable without a cold chain, and massively scalable. Bacillus thuringiensis crystal protein 5B (Cry5B) has anthelmintic properties that could fill this void. Here, we developed an active pharmaceutical ingredient (API) containing B. thuringiensis Cry5B compatible with MDA. We expressed Cry5B in asporogenous B. thuringiensis during vegetative phase, forming cytosolic crystals. These bacteria with cytosolic crystals (BaCC) were rendered inviable (inactivated BaCC [IBaCC]) with food-grade essential oils. IBaCC potency was validated in vitro against nematodes. IBaCC was also potent in vivo against human hookworm infections in hamsters. IBaCC production was successfully scaled to 350 liters at a contract manufacturing facility. A simple fit-for-purpose formulation to protect against stomach digestion and powdered IBaCC were successfully made and used against GINs in hamsters and mice. A pilot histopathology study and blood chemistry workup showed that five daily consecutive doses of 200 mg/kg body weight Cry5B IBaCC (the curative single dose is 40 mg/kg) was nontoxic to hamsters and completely safe. IBaCC is a safe, inexpensive, highly effective, easy-to-manufacture, and scalable anthelmintic that is practical for MDA and represents a new paradigm for treating human GINs.

Radiographic Differentiation of Cranial Mediastinal Lymphomas from Thymic Epithelial Tumors in Dogs and Cats.

In both dogs and cats, the most common cranial mediastinal masses (CMMs) are lymphoma and thymic epithelial tumors (TETs). Pretreatment differentiation of these tumors using fine needle aspiration or biopsy is essential because lymphomas are treated medically, whereas TETs are treated surgically. The purpose of this retrospective study was to determine whether thoracic radiographic findings can be used to aid clinicians in preliminarily differentiating the two tumor types before cytology or histopathology results become available. Medical records, available cytologic or histologic samples, and thoracic radiographs were evaluated for 62 dogs and 28 cats. Seventeen radiographic criteria were assessed by two examiners, and regression modeling was performed to test for significant predictors of tumor type. In dogs, CMMs with at least two well-defined radiographic margins on a lateral view and CMMs causing a rightward shift of the cardiac silhouette on a ventrodorsal or dorsoventral view were significantly more likely to be TETs than lymphomas (P < .001 and P < .01, respectively). No significant predictive variables were identified in cats. Radiographic findings do not eliminate the need for invasive sampling, but in dogs, they may guide the clinician in providing preliminary information to owners regarding the staging and therapeutic measures that may eventually be recommended.

The mechanism for transcriptional activation of the human ATA2 transporter gene by amino acid deprivation is different than that for asparagine synthetase.

After amino acid deprivation, the mRNA content for both asparagine synthetase (AS) and the system A transporter ATA2 is increased. The purpose of the reported experiments was to characterize the molecular mechanism for the ATA2 gene and to contrast the ATA2 regulatory characteristics with those of AS. Amino acid limitation was initiated by incubation of HepG2 human hepatoma cells in either amino acid-free Krebs-Ringer bicarbonate buffer or culture medium lacking the single amino acid histidine. For ATA2, like AS, the elevated mRNA content was due to increased transcription. However, there were fundamental differences between the mechanisms for nutrient regulation of the AS and ATA2 genes. When cells were deprived of amino acids, there was a lag period of approximately 4 h before an increase in AS mRNA occurred, whereas the elevation of ATA2 mRNA was readily detectable at 2-4 h. Consistent with these observations, de novo protein synthesis was absolutely required for the activation of the AS gene, but the increase in ATA2 mRNA was largely independent of protein synthesis. Furthermore, in contrast to AS, transcription from the ATA2 gene was not increased by glucose deprivation. Given this lack of ATA2 transcriptional activation by glucose starvation and that the induction of the AS gene by glucose or amino acid starvation is mediated by common genomic elements, it is likely that the ATA2 gene does not contain the same genomic amino acid-responsive cis-elements as the AS gene.

ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene.

Transcription from the asparagine synthetase (A.S.) gene is increased in response to either amino acid (amino acid response) or glucose (endoplasmic reticulum stress response) deprivation. These two independent pathways converge on the same set of genomic cis-elements within the A.S. promoter referred to as nutrient-sensing response elements (NSRE) 1 and 2, both of which are necessary for gene activation. The NSRE-1 sequence was used to screen ATF/CREB family members by electrophoresis mobility shift assays and supershift by specific antibodies. The results indicated that ATF4 binds to the NSRE-1 sequence and that the amount of the ATF4 complex was increased when extracts from amino acid-deprived or glucose-deprived cells were tested. Using electrophoresis mobility shift assay experiments and a probe that contained both NSRE-1 and NSRE-2, mutation of the NSRE-1 sequence completely prevented formation of the ATF4-containing complexes, whereas mutation of the NSRE-2 sequence did not. Overexpression of ATF4 increased A.S. promoter-driven transcription, whereas an inhibitory dominant negative ATF4 mutant blocked both basal and starvation-enhanced transcription. Collectively, the results provide both in vitro and in vivo evidence for a role of ATF4 in the transcriptional activation of the A.S. gene in response to nutrient deprivation.