Early Blood Profile of C57BL/6 Mice Exposed to Chronic Unpredictable Stress.

Physiological responses to psychological stressors are protective in acute fight or flight situations; however, there is increasing evidence suggesting the detrimental impact of chronic psychological stress on disease. Chronic stress has been associated with inflammation, poor prognosis, increased morbidity, and poor outcome in many diseases including atherosclerosis, cancer, and pulmonary disease. Given the systemic impact of stress, and the role of the hematopoietic system as a rapid responder to homeostatic insults, we hypothesized that early blood profile changes and biochemical alterations could be detected in a model of chronic stress. To test this hypothesis, a variation of the chronic unpredictable stress (CUS) model was employed. Following 10 days of CUS, C57BL/6 mice exhibited a chronic-stress-associated corticosterone profile. Complete blood count (CBC) revealed mild normochromic, normocytic anemia, and reduced monocyte and lymphocyte count. Serum analysis demonstrated hypoferremia with unchanged total iron binding capacity and serum ferritin levels. These findings are consistent with clinical diagnostic parameters for anemia of chronic disease and indicate that CUS results in significant changes in blood and serum biochemical profile in C57BL/6 mice. These studies identify early changes in blood parameters in response to CUS and identify hematopoietic and biochemical alterations that are often associated with increased morbidity in patients experiencing chronic-stress-associated mental health disease.

Localized delivery of therapeutic doxorubicin dose across the canine blood-brain barrier with hyperthermia and temperature sensitive liposomes.

Most drugs cannot penetrate the blood-brain barrier (BBB), greatly limiting the use of anti-cancer agents for brain cancer therapy. Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug in response to hyperthermia (>40 °C). Since hyperthermia also transiently opens the BBB, we hypothesized that localized hyperthermia can achieve drug delivery across the BBB when combined with TSL. TSL-encapsulated doxorubicin (TSL-Dox) was infused intravenously over 30 min at a dose of 0.94 mg/kg in anesthetized beagles (age ∼17 months). Following, a hyperthermia probe was placed 5-10 mm deep through one of four 3-mm skull burr holes. Hyperthermia was performed randomized for 15 or 30 min, at either 45 or 50 °C. Blood was drawn every 30 min to measure TSL-Dox pharmacokinetics. Nonsurvival studies were performed in four dogs, where brain tissue at the hyperthermia location was extracted following treatment to quantify doxorubicin uptake via high-performance liquid chromatography (HPLC) and to visualize cellular uptake via fluorescence microscopy. Survival studies for 6 weeks were performed in five dogs treated by a single hyperthermia application. Local doxorubicin delivery correlated with hyperthermia duration and ranged from 0.11 to 0.74 µg/g of brain tissue at the hyperthermia locations, with undetectable drug uptake in unheated tissue. Fluorescence microscopy demonstrated doxorubicin delivery across the BBB. Histopathology in Haematoxylin & Eosin (H&E) stained samples demonstrated localized damage near the probe. No animals in the survival group demonstrated significant neurological deficits. This study demonstrates that localized doxorubicin delivery to the brain can be facilitated by TSL-Dox with localized hyperthermia with no significant neurological deficits.

Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo.

BACKGROUND: Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating. METHODS: We used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine in vivo studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution. RESULTS: Both in vivo studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. In vivo, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 µg/g to 3.0 µg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug. CONCLUSIONS: Both computer models and in vivo study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems.

Effects of antimicrobial use in agricultural animals on drug-resistant foodborne salmonellosis in humans: A systematic literature review.

Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant meat or dairy-borne non-typhoidal salmonellosis in humans. Based on publications from the United States (U.S.), Canada, and Denmark from January 2010 to July 2014, 858 articles received title and abstract review, 104 met study criteria for full article review with 68 retained for which data are presented. Antibiotic exposure in both cattle and humans found an increased likelihood of Salmonella colonization, whereas in chickens, animals not exposed to antibiotics (organic) were more likely to be Salmonella positive and those that had antibiotic exposure were more likely to harbor antimicrobial resistant Salmonella organisms. In swine literature, only tylosin exposure was examined and no correlation was found among exposure, Salmonella colonization, or antimicrobial resistance. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Salmonella from farm to fork.

Effect of Antimicrobial Use in Agricultural Animals on Drug-resistant Foodborne Campylobacteriosis in Humans: A Systematic Literature Review.

Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant foodborne campylobacteriosis in humans. Based on publications from the United States (U.S.), Canada and Denmark from 2010 to July 2014, 195 articles were retained for abstract review, 50 met study criteria for full article review with 36 retained for which data are presented. Two publications reported increase in macrolide resistance of Campylobacter coli isolated from feces of swine receiving macrolides in feed, and one of these described similar findings for tetracyclines and fluoroquinolones. A study in growing turkeys demonstrated increased macrolide resistance associated with therapeutic dosing with Tylan® in drinking water. One publication linked tetracycline-resistant C. jejuni clone SA in raw cow's milk to a foodborne outbreak in humans. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Campylobacter from farm to fork. Recent literature confirms that on farm antibiotic selection pressure can increase colonization of animals with drug-resistant Campylobacter spp. but is inadequately detailed to establish a causal relationship between use of antimicrobials in agricultural animals and prevalence of drug-resistant foodborne campylobacteriosis in humans.

Thermal Therapy Approaches for Treatment of Brain Tumors in Animals and Humans.

Primary brain tumors are often aggressive, with short survival from time of diagnosis even with standard of care therapies such as surgery, chemotherapy, and radiation therapy. Thermal therapies have been extensively investigated as both primary and adjuvant therapy. Although thermal therapies are not yet widely used clinically, there have been several promising approaches demonstrated in both animals and humans. This review presents thermal therapy approaches in animal and human studies, including both hyperthermia (temperatures ~42°C-45°C) and thermal ablation (temperatures > 50°C). Hyperthermia is primarily used as adjuvant to chemotherapy and radiotherapy, and is the most widely studied radiation sensitizer where enhanced efficacy has been shown in human patients with brain cancer. Hyperthermia has additional beneficial effects such as immunogenic effects, and opening of the bloodbrain barrier to potentially enhance drug delivery, for example in combination with nanoparticle drug delivery systems. Thermal ablation uses high temperatures for direct local tumor destruction, and it found its way into clinical use as laser interstitial thermal therapy (LITT). This review presents various hyperthermia and ablation approaches, including a review of different devices and methods that have been used for thermal therapies, such as radiofrequency/microwaves, laser, high-intensity focused ultrasound, and magnetic nanoparticles. Current research efforts include the combination of advanced thermal therapy devices, such as focused ultrasound with radiation, as well as the use of thermal therapies to enhance chemotherapy delivery across the blood-brain barrier.

Use of a pedicled rectus abdominis muscle flap for repair of a failed vesicourethral anastomosis in a dog.

A 10-year-old mixed breed dog underwent a prostatectomy for an adenocarcinoma. Within three days the dog had signs of a uroperitoneum. Re-exploration revealed that a portion of the vesicourethral anastomosis had failed. Primary suturing of the tissue along the site of dehiscence following debridement of the devitalised tissue was impossible. A rectus abdominis muscle flap was created and successfully used to repair the site of leakage.

Butorphanol tartrate for partial reversal of oxymorphone-induced postoperative respiratory depression in the dog.

A randomized, blinded, crossover study was designed to evaluate the respiratory, cardiovascular, and behavioral effects of butorphanol given postoperatively to oxymorphone-premedicated and surgically stimulated dogs. Nine healthy adult dogs were premedicated intramuscularly with atropine (0.04 mg/kg), acepromazine (0.10 mg/kg), and oxymorphone (0.2 mg/kg). Anesthesia was induced with thiamylal (12 mg/kg) and maintained with halothane in oxygen. According to the protocol of a concurrent study, all dogs had percutaneous endoscopic gastrostomy (PEG) feeding tubes placed during the first anesthetic episode and removed during the second anesthetic episode. All dogs received postoperatively either butorphanol tartrate (0.2 mg/kg) or an isovolumetric dose of saline placebo, both given intravenously. Respiratory rate (RR), tidal volume (TV), minute ventilation (MV), end-tidal CO2 concentration (ETCO2), heart rate (HR), and indirect diastolic (DP), systolic (SP) and mean arterial (MAP) blood pressures were measured at times 0, 2, 5, 10, 20, 40, 80, and 120 minutes after injection. The time from injection of the test drug until extubation was recorded. RR, MV, HR, and DP were significantly (P < .05) increased, while ETCO2 was significantly decreased, for a minimum of 30 minutes in butorphanol-treated dogs compared with saline controls. TV, SP, and MAP were transiently (< or = 15 minutes) increased in butorphanol-treated dogs compared with saline controls. There was no significant difference between the times to extubation in the butorphanol-treated dogs versus the saline control dogs.