Australian adolescents' beliefs and help-seeking intentions towards peers experiencing symptoms of depression and alcohol misuse.

BACKGROUND: Many young people are reluctant to seek professional help for mental health problems, preferring to rely on their friends for support. It is therefore important to ensure that adolescents can identify signs of psychological distress in their peers, talk to them about these, and help them access appropriate services when necessary. The current study examined adolescents' ability to recognise symptoms of depression and alcohol misuse, perceived barriers to help-seeking, and their intentions to encourage a peer to seek help from a range of informal and formal help sources. METHOD: The current study used baseline data from a randomised controlled trial of a school-based intervention that teaches adolescents how to overcome barriers to accessing professional help for mental health and substance use problems (MAKINGtheLINK). Participants (n = 2456) were presented with two vignettes portraying depression and alcohol misuse, respectively, and were asked to identify the problems described. Participants provided data on their past help-seeking behaviour, confidence to help a peer, perceived barriers to help-seeking, and intentions to encourage a peer to seek help. RESULTS: Health professionals were the main source of help that participants had relied on for depressive symptoms, followed by friends and parents. In contrast, friends were the main source of help that participants had relied on for alcohol and other drug problems, followed by health professionals and parents. Just over half of the sample correctly identified the problems described in the two vignettes, although the majority of participants were confident that they could talk to a peer and help them seek professional help if needed. Most agreed that the vignettes described problems that warranted professional help, however approximately half the sample was unsure or considered it unlikely that they would seek help if they experienced similar problems. For both disorders, participants were most likely to encourage a peer to seek help from their family, followed by formal help sources and friends. CONCLUSIONS: While the results point towards a greater willingness to approach formal help sources, particularly for depression, peers remain an important source of support for young people experiencing mental health and substance use problems.

Advocating for Generalizability: Accepting Inherent Variability in Translation of Animal Research Outcomes.

Advancing scientific discovery requires investigators to embrace research practices that increase transparency and disclosure about materials, methods, and outcomes. Several research advocacy and funding organizations have produced guidelines and recommended practices to enhance reproducibility through detailed and rigorous research approaches; however, confusion around vocabulary terms and a lack of adoption of suggested practices have stymied successful implementation. Although reproducibility of research findings cannot be guaranteed due to extensive inherent variables in attempts at experimental repetition, the scientific community can advocate for generalizability in the application of data outcomes to ensure a broad and effective impact on the comparison of animals to translation within human research. This report reviews suggestions, based upon work with National Institutes of Health advisory groups, for improving rigor and transparency in animal research through aspects of experimental design, statistical assessment, and reporting factors to advocate for generalizability in the application of comparative outcomes between animals and humans.

Dilated cardiomyopathy of possible dietary origin in a cat.

An 11-year-old spayed female domestic shorthaired cat was diagnosed with severe dilated cardiomyopathy (DCM) and congestive heart failure. The cat had been eating cat foods that were high in pulses (e.g. peas, lentils, chickpeas). Neither plasma nor whole blood taurine concentrations were deficient. Primary treatment included furosemide, pimobendan, and clopidogrel, and changing to diets that did not contain pulses (a taurine supplements was not administered). The cat's clinical signs improved, high-sensitivity cardiac troponin I concentrations decreased, and echocardiographic measurements stayed relatively stable for over one year after initiating cardiac medications and changing the diet. Ultimately, the cat was euthanized for worsening congestive heart failure 374 days after the diagnosis of DCM. Infectious disease testing during the time of clinical surveillance was negative. Routine histopathology of the heart was unremarkable, but electron microscopy of the left ventricle showed large numbers of mitochondria of variable size and structure. A moderate number of lamellar bodies and autophagic vacuoles also were noted. This case report illustrates an unusual case of a cat with DCM unrelated to taurine deficiency. The relative roles of diet change, cardiac medications, and a dedicated owner are unclear, but this cat's relatively long survival time is similar to that seen after diet change in dogs and cats with DCM eating high-pulse diets.

Bioethical, Reproducibility, and Translational Challenges of Animal Models.

There is no prescribed stage or standardized point at which an animal model protocol is reviewed for reproducibility and translatability. The method of review for a reproducible and translatable study is not consistently documented in peer literature, and this is a major challenge for those working with animal models of human diseases. If the study is ill designed, it is impossible to perform an accurate harm/benefit analysis. In addition, there may be an ethical challenge if the work is not reproducible and translatable. Animal welfare regulations and other documents of control clearly state the role of the Institutional Animal Care and Use Committees are to look at science justification within the context of animal welfare. This article, concentrating on models not governed by regulations, outlines issues and offers recommendations for refining animal model review with a goal to improve study reproducibility and translatability.

The Role of the IACUC in the Design and Conduct of Animal Experiments that Contribute to Translational Success.

Institutional Animal Care and Use Committees (IACUCs) have a mandated role under the Animal Welfare Act and under Public Health Service Policy to assure the ethical and humane use of research animals in experiments conducted in the United States. The IACUC by virtue of its mandated functions is well positioned to help nurture an institutional culture of optimized animal use since this Committee is often responsible in large part for the culture of animal use that evolves within an institution. In addition to fostering a culture of humane care for research animals and a culture of working with the concepts of the 3Rs (refinement, reduction, replacement), the IACUC can help foster a culture of optimized animal use that encourages high quality reproducible studies that contribute to translational success. In part this is achieved when the IACUC is successful in encouraging interdisciplinary collaboration early and often within the animal use community it serves. Unfortunately in some instances the institutional research community may envisage the IACUC as a bureaucratic burden, regulatory necessity, and compliance tool more than a group that enhances the methodology and quality of animal experiments. A well-functioning IACUC should strive to nurture an institutional culture that places value in enhancing the scientific quality of research to help assure the reproducibility of animal studies and translational success of animal models. This is integral to both high quality science as well as excellence in the supporting animal care and use.

Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury.

The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts.

Gene expression analysis of the acute phase response using a canine microarray.

The safety of pharmaceuticals is typically assessed in the dog and rat prior to investigation in humans. As a result, a greater understanding of adverse effects in these preclinical testing species would improve safety assessment. Despite this need, there is a lack of tools to examine mechanisms and identify biomarkers in the dog. To address this issue, we developed an Affymetrix-based oligonucleotide microarray capable of monitoring the expression of thousands of canine genes in parallel. The custom canine array contains 22,774 probe sets, consisting of 13,729 canine and 9045 human-derived probe sets. To improve cross-species hybridization with human-derived probes, the detection region was moved from the variable 3' UTR to the more homologous coding region. Testing of this strategy was accomplished by comparing hybridization of naive dog liver RNA to the canine array (coding region design) and human U133A array (standard 3' design). Although raw signal intensity was greater with canine-specific probe sets, human-derived probes detected the expression of additional liver transcripts. To assess the ability of this tool to detect differential gene expression, the acute phase response was examined in beagle dogs given lipopolysaccharide (LPS). Hepatic gene expression 4 and 24 h post-LPS administration was compared to gene expression profiles of vehicle-treated dogs (n=3/group). Array data was consistent with an acute inflammatory response, with transcripts for multiple cytokines and acute phase proteins markedly induced 4 h after LPS challenge. Robust changes in the expression of transcripts involved with glucose homeostasis, biotransformation, and extracellular matrix remodeling were observed 24 h post-dose. In addition, the canine array identified several potential biomarkers of hepatic inflammation. Strong correlations were found between gene expression data and alterations in clinical chemistry parameters such as serum amyloid A (SAA), albumin, and alkaline phosphatase (ALP). In summary, this new genomic tool successfully detected basal canine gene expression and identified novel aspects of the acute phase response in dog that shed new light on mechanisms underlying inflammatory processes.

Streptococcus agalactiae and Streptococcus difficile 16S-23S intergenic rDNA: genetic homogeneity and species-specific PCR.

Streptococcus difficile is a non-hemolytic Gram-positive bacterial coccus that causes septicemia and meningoencephalitis in farmed tilapia (Oreochromis sp.) and rainbow trout (Oncorhynchus mykiss). Recent studies have demonstrated S. difficile to be a group B, type Ib streptococcus with a whole cell protein electrophoretic profile indistinguishable from S. agalactiae and a biochemical profile similar to that observed for other group B, type Ib streptococci isolated from fish and frogs. The aim of this study was to expand on these findings by comparative nucleic acid sequence analysis of the 16S-23S ribosomal DNA (rDNA) intergenic spacers of S. difficile and S. agalactiae. The 97.7% sequence homology identified in these studies supports the taxonomic relationship of these two organisms. The sequence data generated were also used to construct a pair of species-specific PCR primers for use in molecular detection and identification schemes.

Cooled-tip diode laser catheter for improved catheter ablation of ventricular tachycardia.

Catheter ablation for the treatment of arrhythmias has evolved dramatically over the past two decades. Researchers have investigated alternative energy sources and catheter constructs to improve the efficacy and safety of catheter ablation. This study tested the hypothesis that a new prototype cooled-tip laser catheter used with a low-power diode laser would improve catheter ablation of ventricular tachycardias. Four mongrel dogs underwent a median sternotomy. The cooled-tip laser catheter was advanced into the left ventricle via the left carotid artery and positioned adjacent to the endocardium. Laser powers of 3 and 4 W were delivered at four exposure times to select areas of the endocardium. During application of laser energy, room-temperature saline was circulated through the catheter. At necropsy the hearts were examined and fixed in formalin for histologic examination. Gross examination of the endocardial surfaces showed no indication of crater or thrombus formation. Cross-section of the lesions revealed sharply demarcated, circular-shaped areas of coagulative necrosis extending into the mid-myocardium. Areas of coagulative necrosis were identified within the myocardium extending into the mid-myocardium and occasionally the subepicardium. A sharp line of demarcation was observed between the lesions and the surrounding normal myocardium. The results of this study showed that we could use surface cooling during slow laser heating to create large subsurface lesions with characteristics appropriate for treatment of ventricular tachycardia and little to no surface damage. We believe our catheter system addresses many of the previous issues with laser-based approaches.

Use of virulent hemorrhagic enteritis virus for the induction of colibacillosis in turkeys.

Three hundred fifty 1-day-old large white turkeys were reared in brooding batteries to 10 days of age, after which they were moved to floor pens on litter. At 7 weeks of age, poults were allotted into four treatment groups as follows: 1) virulent hemorrhagic enteritis virus (HEV) alone (100 turkeys), 2) Escherichia coli alone (100 turkeys), 3) HEV + E. coli (100 turkeys), and 4) negative controls (50 turkeys). HEV was given orally at 7 weeks of age, followed by E. coli challenge in the drinking water 2 days later for 10 consecutive days. All groups were observed daily for mortality, both during and after challenge. Turkeys that died or were moribund were necropsied, and cultures were taken from the liver and bone marrow for bacterial isolation. Total mortality rates were 23% in the HEV + E. coli group, 10% in the HEV-only group, 3% in the E. coli-only group, and 0% in the negative control group. Cumulative mortality values were significantly different from those of the negative controls (P < or = 0.05) for HEV only and the HEV + E. coli group. E. coli was isolated from the liver and bone marrow of almost all turkeys that died.

Collateral circulation in experimental coarctation of the aorta in minipigs: a possible association with hypertrophied vasa vasorum.

Experimental coarctation of the thoracic aorta was produced in 13 adult Yucatan minipigs by placing a gradually expanding "C-shaped" occluder around the aorta. The aortic constriction was standardized by measuring the blood pressure above the coarctation, with a mean arterial pressure of 165-170mmHg as the target. The pigs were humanely killed after 8 weeks of hypertension. No deaths were associated with constriction of the aorta, and neither rear limb weakness nor neurological dysfunction was noted. The lack of clinical signs in these animals suggested the development of an extensive collateral circulation. Collateral vessels, which were verified angiographically, included intercostal arteries, muscular intercostal arteries, and the internal thoracic artery. In two of the animals in which the thoracic aorta was completely occluded, revascularization also occurred via small arterial channels. Histologically, there was a marked increase in the number of vessels as well as significant hyperplasia and hypertrophy of smooth muscle of adventitial vasa vasorum. These findings support the hypothesis that collateralization of occluded thoracic aortas may be aided by hypertrophy of the vasa vasorum. To our knowledge, these vessels have not previously been shown convincingly by histopathological methods to revascularize occluded large arteries such as the aorta.

Possible antibiotic-associated colitis in a dog.

A Poodle referred for renal disease developed severe colonic disease characterized by total mucosal collapse and necrosis. The onset of colonic disease was temporally related to administration of antibiotics. On 3 occasions, bacterial culture of fecal samples yielded only Streptococcus pyogenes, Pseudomonas aeruginosa, and Candida albicans, suggesting that the colonic bacterial flora was severely disrupted. Findings, although not conclusive, were suggestive of antibiotic-associated colitis that ultimately proved fatal. Colonoscopy should be considered for dogs with unduly severe large-bowel diarrhea associated with antibiotic treatment and can be done with minimal restraint and bowel preparation, if necessary. Nonselective bacterial culture of fecal samples should be considered for dogs with unduly severe large-bowel diarrhea associated with antibiotic treatment.

Rectal stricture in an ostrich (Struthio camelus).

Exploratory celiotomy of an 18-mo-old female ostrich (Struthio camelus) with anorexia, lethargy, and constipation of 5 days' duration showed mesenteric volvulus and a focal narrowing of the rectum approximately 28 cm cranial to the cloaca. The prognosis was poor and the animal was euthanized. Necropsy revealed a fibrinonecrotic proctitis and a 3-cm-long circumferential stricture of the rectum. Histologically, the rectal wall at the stricture was deeply effaced by fibrovascular connective tissue with vascular thrombosis and necrotizing vasculitis, and it resembled the lesions in feeder pigs with fibrinonecrotic colitis.

Partial tracheal obstruction due to chondromas in ball pythons (Python regius).

Over a 9-mo period, three adult ball pythons (Python regius) (one male, two females) were evaluated for severe dyspnea. Partial obstructions of the tracheal lumen were identified radiographically and/or visualized with a 3.0-mm rigid laparoscope inserted into the tracheal lumen in all three snakes. Administration of systemic antibiotics and nebulization resulted in partial improvement of the dyspnea. In two snakes, the tracheal lesions were removed with a rigid laparoscope and a flexible biopsy instrument inserted into the tracheal lumen. The other snake died and was necropsied. Histologically, the lesions from two snakes were determined to be benign chondromas. The chondromas were composed of a variably disorganized chondroid matrix populated by quiescent, normal-appearing chondrocytes within lacunae, although the chondrocytes were increased in density compared with normal hyaline cartilage and contained rare mitotic figures. The tracheal masses in one snake grew by expansion, not invasion, and were focally continuous with a mineralized cartilage tracheal ring, suggesting a benign nature. This is the second report of tracheal chondroma in ball pythons. Tracheal chondromas are exceedingly rare in humans and domesticated animals, suggesting a possible predisposition of ball pythons for this neoplasm.

Characterization of the genetic basis for autosomal recessive hereditary nephropathy in the English Springer Spaniel.

BACKGROUND: Autosomal recessive hereditary nephropathy (ARHN) was diagnosed in 2 English Springer Spaniels (ESS), a breed not previously reported to be affected by hereditary nephropathy (HN). OBJECTIVE: To identify and characterize the genetic cause of ARHN in ESS. ANIMALS: Sixty-three ESS (2 with ARHN, 2 obligate carriers, and 59 others), 2 mixed-breed dogs with X-linked HN, and 2 English Cocker Spaniels (ECS) with ARHN were included. METHODS: ARHN was diagnosed based on transmission electron microscopy and immunostaining of kidney. DNA from affected dogs was screened for the mutation known to cause ARHN in ECS. Quantities of COL4A3, COL4A4, and COL4A5 mRNA transcripts in renal cortex were determined using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for ARHN-affected dogs and 7 other dogs. The coding regions of COL4A3 and COL4A4 were sequenced for the 2 ARHN-affected ESS and an unaffected dog. Exon 30 of COL4A4 was sequenced for all 63 ESS. RESULTS: qRT-PCR indicated a significant reduction in transcript levels of both COL4A3 and COL4A4 mRNA in the kidney of ARHN-affected ESS. Sequencing identified a single nucleotide substitution in COL4A4 at base 2806 resulting in a premature stop codon. Thirteen of 25 related dogs were identified as carriers. CONCLUSIONS AND CLINICAL IMPORTANCE: A mutation highly likely to cause ARHN in ESS has been identified.

A call for more integrated cardiovascular safety assessment.

Cardiovascular safety concerns are a significant cause of attrition in the development of new drugs (Lasser et al., 2002). This attrition has significant public health implications and also contributes to the rising cost of developing new drugs. However, a better understanding of the inter-relationship between nonclinical and clinical predictors/measures of cardiovascular risk as well as a more integrated and predictive development strategy could dramatically augment the development of safe and effective medicines for patients in need. In response to this need, a consortium of industrial, academic, and government scientists designed and executed a three day 'think tank' under the auspices of the non-profit ILSI Health and Environmental Sciences Institute (ILSI HESI) in June 2009 in Washington, D.C. This highly interactive scientific forum provided a unique opportunity for experts with diverse cardiovascular-related expertise to collectively discuss issues, challenges, and opportunities to improve the overall pharmaceutical cardiovascular safety assessment paradigm. This article identifies the major points of consensus and recommendations stemming from this workshop.

Small intestine large granular lymphoma in a horse.

A 12-year-old Appaloosa gelding was referred to the Texas Veterinary Medical Center with a history of chronic diarrhea and weight loss. At necropsy, numerous oval, craterlike ulcers were observed throughout the small intestine. Histologically, these lesions were composed of a neoplastic proliferation of round cells with intracytoplasmic phosphotungstic acid-hematoxylin-positive granules. The tumor cells stained positively for the CD3 antigen and negatively for a B-cell marker. A diagnosis of large granular lymphoma was based on the morphologic and immunohistochemical characteristics of the neoplasm. The postmortem presentation of this case depicted unusual multifocal, ulcerative lymphomatous lesions throughout the small intestine without involvement of the regional lymph nodes. The histologic and ultrastructural morphology of the neoplastic lymphocytes was similar to that in previously reported cases of abdominal equine large granular lymphomas, but in this case the neoplasm was restricted to the small intestine.

Evaluation of postoperative peritoneal lavage in standing horses for prevention of experimentally induced abdominal adhesions.

OBJECTIVE: To evaluate the postoperative use of peritoneal lavage for prevention of experimentally induced intraabdominal adhesions in horses. STUDY DESIGN: Areas of serosal abrasion were created on the jejunum of 12 horses. Postoperatively, six horses had peritoneal lavage, and six horses did not (controls). The number of adhesions was determined at necropsy 2 weeks after surgery. ANIMALS OR SAMPLE POPULATION: 12 horses. METHODS: Five sites of jejunal serosal abrasion were created in each horse. A 32 French thoracic catheter was placed into the right ventral aspect of the abdomen before closure of the abdominal incision. Treated horses had abdominal lavage with 10 L of lactated Ringer's solution on four occasions, then catheters were removed from all horses 34 hours after celiotomy. Horses were necropsied at 2 weeks to quantify the number of intraabdominal adhesions. RESULTS: All control horses and one treated horse developed intraabdominal adhesions. The number of adhesions was significantly less (P < .0293) in treated horses. No adverse inflammatory reactions appeared to be associated with repeated peritoneal lavage using lactated Ringer's solution or use of an abdominal drain. CONCLUSIONS: Peritoneal lavage reduced the frequency of intraabdominal adhesions. CLINICAL RELEVANCE: When postoperative adhesions are likely to develop, postoperative peritoneal lavage may decrease the frequency of adhesion formation.