Lack of Interference of Oclacitinib with the results of intradermal testing or allergen-specific IgE serology in Dermatophagoides farinae-sensitized beagle dogs.

Canine atopic dermatitis (AD) is associated with increased levels of allergen-specific IgE due to hyper-sensitization to environmental allergens. Intradermal testing (IDT) and allergen-specific IgE serology testing are often used to determine the allergens which elicit an IgE response in animals with a diagnosis of AD. The objective of this study was to determine the effects of oclacitinib on IDT and allergen-specific IgE serology testing using a laboratory model of house-dust mite sensitized Beagle dogs. Twenty-four (24) normal, healthy purpose-bred Beagle dogs were sensitized to house dust mites (HDM, Dermatophagoides farinae) and randomly assigned to placebo-, oclacitinib- (0.4 mg/kg/dose PO), or prednisolone-treated (0.5 mg/kg/dose PO) groups. After 14 days of twice daily dosing, the effects of prednisolone and oclacitinib were compared to placebo using baseline and post-dose IDT and allergen-specific IgE serum measurements. Sensitized dogs had increased circulating HDM-specific IgE for at least two weeks post-sensitization. Prednisolone significantly inhibited the measurable sensitivity of IDT, while oclacitinib did not. Neither prednisolone nor oclacitinib imposed significant effects on allergen-specific IgE serum levels, suggesting oclacitinib may have potential to be used in dogs concurrently undergoing intradermal skin testing and/or allergen-specific IgE serology testing without interference with test results.

Genomics analysis of hexanoic acid exposure in Drosophila species.

Drosophila sechellia is a dietary specialist endemic to the Seychelles islands that has evolved to consume the fruit of Morinda citrifolia. When ripe, the fruit of M. citrifolia contains octanoic acid and hexanoic acid, two medium-chain fatty acid volatiles that deter and are toxic to generalist insects. Drosophila sechellia has evolved resistance to these volatiles allowing it to feed almost exclusively on this host plant. The genetic basis of octanoic acid resistance has been the focus of multiple recent studies, but the mechanisms that govern hexanoic acid resistance in D. sechellia remain unknown. To understand how D. sechellia has evolved to specialize on M. citrifolia fruit and avoid the toxic effects of hexanoic acid, we exposed adult D. sechellia, D. melanogaster and D. simulans to hexanoic acid and performed RNA sequencing comparing their transcriptional responses to identify D. sechellia specific responses. Our analysis identified many more genes responding transcriptionally to hexanoic acid in the susceptible generalist species than in the specialist D. sechellia. Interrogation of the sets of differentially expressed genes showed that generalists regulated the expression of many genes involved in metabolism and detoxification whereas the specialist primarily downregulated genes involved in the innate immunity. Using these data, we have identified interesting candidate genes that may be critically important in aspects of adaptation to their food source that contains high concentrations of HA. Understanding how gene expression evolves during dietary specialization is crucial for our understanding of how ecological communities are built and how evolution shapes trophic interactions.

Impact of Medical Blog Reading and Information Presentation on Readers' Preventative Health Intentions: Mixed Methods, Multistudy Investigation.

BACKGROUND: Medical blogs have become valuable information sources for patients and caregivers. Most research has focused on patients' creation of blogs as therapy. But we know less about how these blogs affect their readers and what format of information influences readers to take preventative health actions. OBJECTIVE: This study aimed to identify how reading patient medical blogs influences readers' perceived health risk and their intentions to engage in preventative health actions. Further, we aimed to examine the format of the medical blog and the reader's response. METHODS: We surveyed 99 university participants and a general-population, online panel of 167 participants. Both studies randomly assigned participants to conditions and measured blog evaluation, intentions for preventative health action, and evaluation of health risk and beliefs, and allowed open-ended comments. The second study used a different sample and added a control condition. A third study used a convenience sample of blog readers to evaluate the link between reading medical blogs and taking preventative health action. RESULTS: Across 3 studies, participants indicated a desire to take future preventative health action after reading patient blogs. Studies 1 and 2 used experimental scenario-based designs, while Study 3 employed a qualitative design with real blog readers. The 2 experimental studies showed that the type of blog impacted intentions to engage in future preventative health actions (Study 1: F2,96=6.08, P=.003; Study 2: F3,166=2.59, P=.06), with a statistical blog being most effective in both studies and a personal narrative blog showing similar effectiveness in Study 2, contrary to some prior research. The readers' perceptions of their own health risk did not impact the relationship between the blog type and health intentions. In contrast, in one study, participants' judgments about the barriers they might face to accessing care improved the fit of the model (F2,95=13.57, P<.001). In Study 3's sample of medical blog readers, 53% (24/45) reported taking preventative health action after reading a health blog, including performing a self-check, asking a doctor about their health risk, or requesting a screening test. Additionally, these readers expressed that they read the blogs to follow the author (patient) and to learn general health information. All studies demonstrated the blogs were somewhat sad and emotional but also informative and well-written. They noted that the blogs made them appreciate life more and motivated them to consider taking some action regarding their health. CONCLUSIONS: Reading patient blogs influences intentions to take future health actions. However, blog formats show different efficacy, and the readers' disease risk perceptions do not. Physicians, medical practitioners, and health organizations may find it useful to curate or promote selected medical blogs to influence patient behavior.

Primary age-related tauopathy (PART) in the general autopsy setting: Not just a disease of the elderly.

Primary age-related tauopathy (PART) is generally considered a diagnosis of the elderly. In this letter, the authors present data showing that the pathologic changes of PART can occur in the general autopsy population significantly earlier than largely reported in the recent literature, particularly in woman.

The Aerogen® Solo Is an Alternative to the Small Particle Aerosol Generator (SPAG-2) for Administration of Inhaled Ribavirin.

Respiratory syncytial virus (RSV) is associated with adverse outcomes among immunocompromised patients. Inhaled ribavirin has been shown to improve mortality rates. The Small-Particle Aerosol Generator delivery system (SPAG-2) is the only FDA-cleared device to deliver inhaled ribavirin. However, it is difficult to set up and maintain. We developed a method for delivery of this medication using the vibrating mesh nebulizer (Aerogen®). We did not observe any adverse events with this method.

COVID-19: Postmortem Diagnostic and Biosafety Considerations.

As a result of the 2019 novel human coronavirus (COVID-19) global spread, medical examiner/coroner offices will inevitably encounter increased numbers of COVID-19-infected decedents at autopsy. While in some cases a history of fever and/or respiratory distress (eg, cough or shortness of breath) may suggest the diagnosis, epidemiologic studies indicate that the majority of individuals infected with COVID-19 develop mild to no symptoms. Those dying with-but not of-COVID-19 may still be infectious, however. While multiple guidelines have been issued regarding autopsy protocol in cases of suspected COVID-19 deaths, there is some variability in the recommendations. Additionally, limited recommendations to date have been issued regarding scene investigative protocol, and there is a paucity of publications characterizing COVID-19 postmortem gross and histologic findings. A case of sudden unexpected death due to COVID-19 is presented as a means of illustrating common autopsy findings, as well as diagnostic and biosafety considerations. We also review and summarize the current COVID-19 literature in an effort to provide practical evidence-based biosafety guidance for medical examiner-coroner offices encountering COVID-19 at autopsy.

IL-31-induced pruritus in dogs: a novel experimental model to evaluate anti-pruritic effects of canine therapeutics.

BACKGROUND: Pruritus is a characteristic clinical sign of allergic skin conditions including atopic dermatitis (AD) in the dog. IL-31 is a cytokine found in the serum of some dogs with AD and can induce pruritic behaviours in laboratory beagle dogs. HYPOTHESIS/OBJECTIVES: The objectives were to characterize an IL-31-induced pruritus model by evaluating the efficacy of prednisolone, dexamethasone and oclacitinib, and to compare the speed of anti-pruritic effects of oclacitinib against those of prednisolone and dexamethasone. ANIMALS: Purpose-bred beagle dogs were used in all studies. METHODS: Randomized, blinded, placebo-controlled studies were designed to evaluate and compare the anti-pruritic properties of prednisolone, dexamethasone and oclacitinib following a single intravenous injection of recombinant canine IL-31. Video surveillance was used to monitor and score pruritic behaviours in study animals. RESULTS: Prednisolone [0.5 mg/kg, per os (p.o.)] reduced IL-31-induced pruritus when given 10 h prior to observation. When the time interval between drug treatment and observation was shortened to 1 h, dexamethasone (0.2 mg/kg, intramuscular) but not prednisolone (0.25 or 0.5 mg/kg, p.o.) reduced IL-31-induced pruritus. Oclacitinib (0.4 mg/kg, p.o.) reduced pruritus when given 1, 6, 11 and 16 h prior to the observation period, and the anti-pruritic activity of oclacitinib was greater when compared to prednisolone and dexamethasone at all time points assessed. CONCLUSION AND CLINICAL IMPORTANCE: The efficacy of prednisolone, dexamethasone and oclacitinib in the IL-31-induced pruritus model gives confidence that this may be a relevant model for acute pruritus associated with allergic dermatitis including AD and can be used to evaluate novel compounds or formulations.

Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis.

BACKGROUND: Interleukin-31 (IL-31) is a member of the gp130/interleukin-6 cytokine family that is produced by cell types such as T helper 2 lymphocytes and cutaneous lymphocyte antigen positive skin homing T cells. When overexpressed in transgenic mice, IL-31 induces severe pruritus, alopecia and skin lesions. In humans, IL-31 serum levels correlate with the severity of atopic dermatitis in adults and children. HYPOTHESIS/OBJECTIVE: To determine the role of IL-31 in canine pruritus and naturally occurring canine atopic dermatitis (AD). ANIMALS: Purpose-bred beagle dogs were used for laboratory studies. Serum samples were obtained from laboratory animals, nondiseased client-owned dogs and client-owned dogs diagnosed with naturally occurring AD. METHODS: Purpose-bred beagle dogs were administered canine interleukin-31 (cIL-31) via several routes (intravenous, subcutaneous or intradermal), and pruritic behaviour was observed/quantified via video monitoring. Quantitative immunoassay techniques were employed to measure serum levels of cIL-31 in dogs. RESULTS: Injection of cIL-31 into laboratory beagle dogs caused transient episodes of pruritic behaviour regardless of the route of administration. When evaluated over a 2 h period, dogs receiving cIL-31 exhibited a significant increase in pruritic behaviour compared with dogs that received placebo. In addition, cIL-31 levels were detectable in 57% of dogs with naturally occurring AD (≥ 13 pg/mL) but were below limits of quantification (<13 pg/mL) in normal, nondiseased laboratory or client-owned animals. CONCLUSIONS: Canine IL-31 induced pruritic behaviours in dogs. Canine IL-31 was detected in the majority of dogs with naturally occurring AD, suggesting that this cytokine may play an important role in pruritic allergic skin conditions, such as atopic dermatitis, in this species.

Effect of refrigeration of the antiemetic Cerenia (maropitant) on pain on injection.

Injection pain has been associated with veterinary use of the antiemetic maropitant (Cerenia, Pfizer Animal Health). Cerenia is formulated using sulphobutylether-beta-cyclodextrin to bind maropitant and mitigate injection pain. The objective of this study was to determine whether the temperature of Cerenia alters binding between maropitant and sulphobutylether-beta-cyclodextrin and affects injection pain. Binding decreased as temperature increased, and Cerenia-elicited injection pain increased at warmer drug temperatures. These data suggest that the amount of free unbound maropitant increases with temperature and that injection pain increases with temperature in a similar fashion. Clinically, these studies suggest that injection of refrigerated Cerenia may significantly reduce or eliminate pain associated with SC injection of Cerenia.

Pharmacokinetics and efficacy of linezolid in a gerbil model of Streptococcus pneumoniae-induced acute otitis media.

The oxazolidinone linezolid represents a new antibacterial class of potential benefit in managing multidrug-resistant gram-positive infections, including those caused by Streptococcus pneumoniae. In a gerbil model of acute otitis media (AOM) induced by either penicillin-resistant S. pneumoniae (PRSP; amoxicillin MIC = 8 micro g/ml, linezolid MIC = 1 micro g/ml) or penicillin-susceptible S. pneumoniae (PSSP; amoxicillin MIC = 0.015 micro g/ml, linezolid MIC = 1 micro g/ml), we explored the plasma and ear fluid levels of linezolid required to demonstrate efficacy. Threshold pathogen doses required to induce bilateral AOM (1,500 CFU/ear with PRSP; 30 CFU/ear with PSSP) were administered to gerbils by intrabullar injection on day 0. At peak infection ( approximately 10(6) to 10(7) CFU/ear flush; day 2 for PRSP-AOM and day 3 for PSSP-AOM), twice-a-day oral doses of linezolid, amoxicillin, or vehicle were administered over 4.5 days prior to collection and assay of middle ear effluents for S. pneumoniae content. Linezolid doses of >/=10 mg/kg of body weight induced significant cure rates of >/=72% versus both PRSP and PSSP infections, whereas amoxicillin at MIC of >/=42%, a C(max)/MIC ratio of >/=3.1, and a (24-h area under the curve)/MIC ratio of >/=30 h. Application of this model will be useful in defining preclinical pharmacodynamic relationships of novel antibiotics necessary to cure S. pneumoniae-induced AOM.

Substituted pyrazolopyridopyridazines as orally bioavailable potent and selective PDE5 inhibitors: potential agents for treatment of erectile dysfunction.

Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.

The effects of excitotoxic hippocampal lesions in rats on risperidone- and olanzapine-induced locomotor suppression.

Previous studies have shown that excitotoxic hippocampal lesions in rats attenuate the ability of different doses of haloperidol, but not of clozapine, to suppress locomotor activity. The purpose of the present study was to determine if kainic acid-induced hippocampal damage reduces the degree of locomotor suppression produced by two relatively newer antipsychotic drugs, risperidone and olanzapine. Young adult male rats received bilateral intracerebroventricular infusions of the excitotoxin, kainic acid (KA), or vehicle and were tested for locomotor responses to drug treatment 30 days later. Infusions of KA produced neuronal loss in the CA3 region of the dorsal hippocampus in every rat. As reported previously, KA lesions reduced the ability of haloperidol (0.35 mg/kg) to completely suppress the locomotor activity elicited by amphetamine (1.5 mg/kg) relative to the effect of haloperidol in non-lesioned controls. Lesioned animals treated with a moderate dose of risperidone (1.4 mg/kg) also exhibited significantly more locomotor activity after amphetamine treatment in comparison to control animals. A trend toward greater activity was also observed in the lesioned group relative to the control group after olanzapine (3.0 mg/kg) injection (p =.09, 2-tailed). The locomotor effects of lower and higher doses of risperidone and olanzapine were not altered by kainic acid lesions. These data suggest that the locomotor-suppressive effects of moderate doses of risperidone and, perhaps, olanzapine involve hippocampal neurons, but that higher doses of each drug can suppress activity in a hippocampal-independent manner.

Immediate and delayed hippocampal neuronal loss induced by kainic acid during early postnatal development in the rat.

The degree to which the neonatal hippocampus is resistant to the effects of excitotoxins, such as kainic acid (KA) remains uncertain. Previously, we showed delayed loss of hippocampal neurons during pubescence in neonatal rats subjected to intracerebroventricular (i.c.v.) KA administration (10 nmol) at postnatal day 7 (P7). To further characterize the time course as well as the underlying mechanisms of this neuronal loss, we administered i.c.v. KA (10 or 50 nmol) to P7 preweanling rats. Brain sections were then examined at several neurodevelopmental time points (i.e., P8, P14, P25, P40, P60 and P75) using thionin staining and three-dimensional, non-biased cell counting to assess neuronal loss, and immunohistochemistry and electron microscopy to search for evidence of necrosis and apoptosis. Dose-dependent acute neuronal loss was observed at P8-P14 in hippocampal subfields CA3a and CA3c. Transient heat shock protein (HSP-70) immunostaining accompanied this acute neuronal loss. Progressive neuronal loss then continued in CA3 until P75, but without concomitant HSP-70 immunostaining. Progressive neuronal cell loss was also observed in the CA1 subfield of the hippocampus beginning at pubescence (i.e., P40) and continuing until P75. The appearance of TUNEL-positive hippocampal neurons accompanied the delayed neuronal loss in both CA3 and CA1 and electron micrographs confirmed that neurons in these subfields were undergoing apoptosis. KA administration (i.c.v.) to preweanling rats caused both immediate and delayed damage to hippocampal neurons. The effect of KA was dose-dependent, and the delayed neuronal damage occurred through an apoptosis-mediated mechanism. These findings may be relevant to the pathogenesis of some neuropsychiatric disorders, where early CNS injury is not apparent until the onset of clinical symptoms in young adulthood.