An experimental study on anisotropic mechanical properties of porcine thoracic aorta

Objective: To study the anisotropic mechanical properties of the thoracic aorta in porcine. Methods: Twenty-one porcine thoracic aortas were collected and categorized into three groups. The aortas were then cut through in their axial directions and expanded into two-dimensional planes. Then, by setting the length direction of the planar aortas (i.e., axial directions of the aortas) as 0°, each planar aorta was counterclockwisely cut into 8 samples with orientation of 30°, 45°, 60°, 90°, 120°, 135°, 150° and 180°, respectively. Finally, the uniaxial tensile tests were applied on three groups of samples at the loading rates of 1, 5 and 10 mm/min, respectively, to obtain the elastic modulus and ultimate stress of the aorta in different directions and at different loading rates. Results: The stress-strain curves exhibited different viscoelastic behaviors. With the increase of sample orientations, the elastic modulus gradually increased from 30°, reached the maximum value at 90°, and then gradually decreased till 180°. The variation trend of ultimate stress was similar to that of elastic modulus. Moreover, different loading rates showed a significant influence on the results of elastic modulus and ultimate stress, but a weak influence on the anisotropic degree. Conclusions: The porcine thoracic aorta is highly anisotropic. This research finding provides parameter references for assignment of material properties in finite element modeling, and is significant for understanding biomechanical properties of the arteries.

Patterns of care: Primary research in mental health nursing

The foundation of mental health nursing has historically been grounded in an interpersonal, person-centred process of health care, yet recent evidence suggests that the interactional work of mental health nursing is being eroded. Literature emphasises the importance of person-centred care on consumer outcomes, a model reliant upon the intimate engagement of nurses and consumers. Yet, the arrival of medical interventions in psychiatry has diverted nursing work from the therapeutic nursing role to task-based roles delegated by medicine, distancing nurses from consumers. This study used work sampling methodology to observe the proportion of time nurses working in an inpatient mental health setting engage in specific activities. The observations of this study determined that nurses' time is accounted for 31.65% in direct care, 51.63% in indirect care and 16.71% in service related activities.

Evaluation of the immunogenicity of the P97R1 adhesin of Mycoplasma hyopneumoniae as a mucosal vaccine in mice.

The immunogenicity of P97 adhesin repeat region R1 (P97R1) of Mycoplasma hyopneumoniae, an important pathogenesis-associated region of P97, was evaluated in mice as a mucosal vaccine. Mice were immunized orally with attenuated Salmonella typhimurium aroA strain CS332 harbouring a eukaryotic or prokaryotic expression vector encoding IP97R1. Local and systemic immune responses were analysed by ELISA on mouse sera, lung washes and splenocyte supernatants following splenocyte stimulation with specific antigens in vitro. Although no P97R1-specific antibody responses were detected in serum and lung washes, significant gamma interferon was produced by P97R1-stimulated splenocytes from mice immunized orally with S. typhimurium aroA harbouring either expression system, indicating induction of a cell-mediated immune response. These results suggested that live bacterial vectors carrying DNA vaccines or expressing heterologous antigens preferentially induce a Th1 response. Surprisingly, however, mice immunized with the vaccine carrier S. typhimurium aroA CS332 induced serum IgG, but not mucosal IgA, against P97R1 or S. typhimurium aroA CS332 whole-cell lysate, emphasizing the importance of assessing the suitability of attenuated S. typhimurium antigen-carrier delivery vectors in the mouse model prior to their evaluation as potential vaccines in the target species, which in this instance was pigs.

Morphology-based interslice interpolation on manual segmentations of joint bones and muscles in MRI

This paper presents a validation study on the application of a novel interslice interpolation technique for musculoskeletal structure segmentation of articulated joints and muscles on human magnetic resonance imaging data. The interpolation technique is based on morphological shape-based interpolation combined with intensity based voxel classification. Shape-based interpolation in the absence of the original intensity image has been investigated intensively. However, in some applications of medical image analysis, the intensity image of the slice to be interpolated is available. For example, when manual segmentation is conducted on selected slices, the segmentation on those unselected slices can be obtained by interpolation. We proposed a two- step interpolation method to utilize both the shape information in the manual segmentation and local intensity information in the image. The method was tested on segmentations of knee, hip and shoulder joint bones and hamstring muscles. The results were compared with two existing interpolation methods. Based on the calculated Dice similarity coefficient and normalized error rate, the proposed method outperformed the other two methods.

Inbreeding and the incidence of childhood genetic disorders in Karnataka, South India

Consanguineous marriages are strongly favoured among the populations of South India. In a study conducted on 407 infants and children, a total of 35 genetic diseases was diagnosed in 63 persons: 44 with single gene defects, 12 with polygenic disorders, and seven with Down's syndrome. The coefficient of inbreeding of the total study group, F = 0.0414, was significantly higher than that previously calculated for the general population, F = 0.0271, and autosomal recessive disorders formed the largest single disease category diagnosed. The results suggest that long term inbreeding may not have resulted in appreciable elimination of recessive lethals and sub-lethals from the gene pool.

"Like a monkey with a miniature cymbal": Cultural practices of repetition in visual social media

Looping media are recurring components of online content, from gifs to Vine videos, in addition to the conceptual repetition of memes and related practices. This paper analyses practices around looping visual media as examples of vernacular creativity, social media literacies, and internet culture, especially for irreverent and playful purposes. Focusing on the LGBTQ digital cultural context as a pilot study, this research examines multi-platform uses of looping media, including personal narratives through Vine videos and animated gifs on Tumblr. In addition to textual analysis of LGBTQ looping visual social media content, the study will further explore the platform context as part of the experience of looped media. The research will address how these factors may also contribute to practices of irreverence and play, both within the specific case of LGBTQ culture and internet culture more generally.

Evaluation of an intervention for patients with alcohol-related injuries: results of a mixed methods study

Objective: To explore the effect of education and training on the delivery of alcohol screening and brief intervention and referral to high-risk patients in a hospital setting. Main outcome measures included; delivery of training; practice change in relation to staff performing alcohol screening, brief intervention and referrals. Methods: Observational study design using mixed methods set in a tertiary referral hospital. Pre-post assessment of medical records and semi-structured interviews with key informants. Results: Routine screening for substance misuse (9% pre / 71.4% post) and wellbeing concerns (6.6% pre / 15 % post) was more frequent following the introduction of resources and staff participation in educational workshops. There was no evidence of a concomitant increase in delivery of brief intervention or referrals to services. Implementation challenges, including time constraints and staff attitudes, and enablers such as collaboration and visible pathways, were identified. Conclusion: Rates of patient screening increased, however barriers to delivery of brief intervention and referrals remained. Implementation strategies targeting specific barriers and enablers to introducing interventions are both required to improve the application of secondary prevention for patients in acute settings. Implications: Educational training, formalised liaison between services, systematised early intervention protocols, and continuous quality improvement processes will progress service delivery in this area.

Automatic ICD-10 classification of cancers from free-text death certificates

Objective Death certificates provide an invaluable source for cancer mortality statistics; however, this value can only be realised if accurate, quantitative data can be extracted from certificates – an aim hampered by both the volume and variable nature of certificates written in natural language. This paper proposes an automatic classification system for identifying cancer related causes of death from death certificates. Methods Detailed features, including terms, n-grams and SNOMED CT concepts were extracted from a collection of 447,336 death certificates. These features were used to train Support Vector Machine classifiers (one classifier for each cancer type). The classifiers were deployed in a cascaded architecture: the first level identified the presence of cancer (i.e., binary cancer/nocancer) and the second level identified the type of cancer (according to the ICD-10 classification system). A held-out test set was used to evaluate the effectiveness of the classifiers according to precision, recall and F-measure. In addition, detailed feature analysis was performed to reveal the characteristics of a successful cancer classification model. Results The system was highly effective at identifying cancer as the underlying cause of death (F-measure 0.94). The system was also effective at determining the type of cancer for common cancers (F-measure 0.7). Rare cancers, for which there was little training data, were difficult to classify accurately (F-measure 0.12). Factors influencing performance were the amount of training data and certain ambiguous cancers (e.g., those in the stomach region). The feature analysis revealed a combination of features were important for cancer type classification, with SNOMED CT concept and oncology specific morphology features proving the most valuable. Conclusion The system proposed in this study provides automatic identification and characterisation of cancers from large collections of free-text death certificates. This allows organisations such as Cancer Registries to monitor and report on cancer mortality in a timely and accurate manner. In addition, the methods and findings are generally applicable beyond cancer classification and to other sources of medical text besides death certificates.

Choosing a model of maternity care: decision support needs of Australian women

- BACKGROUND Access to information on the features and outcomes associated with the various models of maternity care available in Australia is vital for women's informed decision-making. This study sought to identify women's preferences for information access and decision-making involvement, as well as their priority information needs, for model of care decision-making. - METHODS A convenience sample of adult women of childbearing age in Queensland, Australia were recruited to complete an online survey assessing their model of care decision support needs. Knowledge on models of care and socio-demographic characteristics were also assessed. - RESULTS Altogether, 641 women provided usable survey data. Of these women, 26.7 percent had heard of all available models of care before starting the survey. Most women wanted access to information on models of care (90.4%) and an active role in decision-making (99.0%). Nine priority information needs were identified: cost, access to choice of mode of birth and care provider, after hours provider contact, continuity of carer in labor/birth, mobility during labor, discussion of the pros/cons of medical procedures, rates of skin-to-skin contact after birth, and availability at a preferred birth location. This information encompassed the priority needs of women across age, birth history, and insurance status subgroups. - CONCLUSIONS This study demonstrates Australian women's unmet needs for information that supports them to effectively compare available options for model of maternity care. Findings provide clear direction on what information should be prioritized and ideal channels for information access to support quality decision-making in practice.

The Pharmacology of Oxycodone : Studies In Vitro, In Vivo and In Humans

The antinociceptive properties of oxycodone and its metabolites were studied in models of thermal and mechanical nociception and in the spinal nerve ligation (SNL) model of neuropathic pain in rats. Oxycodone induced potent antinociception after subcutaneous (s.c.) administration in all models of nociception used in rats compared with morphine, methadone and its enantiomers. In the SNL model of neuropathic pain in rats, oxycodone produced dose dependent antinociception after s.c. administration. The antinociceptive effects of s.c. oxycodone were antagonized by naloxone but not by nor-binaltorphimine (Nor-BNI) a selective κ-opioid receptor antagonist indicating that the antinociceptive properties of oxycodone are predominantly μ-opioid receptor-mediated. The antinociceptive activity of oxymorphone, noroxycodone, and noroxymorphone, oxidative metabolites of oxycodone, were studied to determine their role in the oxycodone-induced antinociception in the rat. Of the metabolites of oxycodone s.c. administration of oxymorphone produced potent thermal and mechanical antinociception. Noroxycodone had a poor antinociceptive effect and noroxymorphone was inactive. Oxycodone produced naloxone-reversible antinociception after intrathecal (i.t) administration with a poor potency compared with morphine and oxymorphone. This seems to be related to the low efficacy and potency of oxycodone to stimulate μ-opioid receptor activation in the spinal cord in μ-opioid receptor agonist-stimulated (GTP)γ[S] autoradiography, compared with morphine and oxymorphone. All metabolites studied were more potent than oxycodone after i.t. administration. I.t. noroxymorphone induced a significantly longer lasting antinociceptive effect compared with the other drugs studied. The role of cytochrome P450 (CYP) 2D6-mediated metabolites on the analgesic activity of oxycodone in humans was studied by blocking the CYP2D6-mediated metabolism of oxycodone with paroxetine. Paroxetine co-administration had no effect on the analgesic effect of oxycodone compared with placebo in chronic pain patients, indicating that oxycodone-induced analgesia and adverse-effects are not dependent of the CYP2D6-mediated metabolism in humans. Although oxycodone has many pharmacologically active metabolites, they seem to have an insignificant role in oxycodone-induced antinociception in humans and rats.

A genome-wide association study of sleep habits and insomnia

Several aspects of sleep behavior such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of six sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317, 370, and 610K arrays and the SNPs in common between platforms were used to impute non-genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the third intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (P = 1.3 x 10(-)(6)). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (P = 0.73). We have identified several other suggestive associations that await replication in an independent sample. We did not replicate the results from previous genome-wide analyses of self-reported sleep phenotypes after correction for multiple testing.

Identification of two novel human neuronal ceroid lipofuscinosis genes

The neuronal ceroid lipofuscinoses (NCLs) are a group of mostly autosomal recessively inherited neurodegenerative disorders. The aim of this thesis was to characterize the molecular genetic bases of these, previously genetically undetermined, NCL forms. Congenital NCL is the most aggressive form of NCLs. Previously, a mutation in the cathepsin D (CTSD) gene was shown to cause congenital NCL in sheep. Based on the close resemblance of the phenotypes between congenital NCLs in sheep and human, CTSD was considered as a potential candidate gene in humans as well. When screened for mutations by sequencing, a homozygous nucleotide duplication creating a premature stop codon was identified in CTSD in one family with congenital NCL. While in vitro the overexpressed truncated mutant protein was stable although inactive, the absence of CTSD staining in brain tissue samples of patients indicated degradation of the mutant CTSD in vivo. A lack of CTSD staining was detected also in another, unrelated family with congenital NCL. These results imply that CTSD deficiency underlies congenital NCL. While initially Turkish vLINCL was considered a distinct genetic entity (CLN7), mutations in the CLN8 gene were later reported to account for the disease in a subset of Turkish patients with vLINCL. To further dissect the genetic basis of the disease, all known NCL genes were screened for homozygosity by haplotype analysis of microsatellite markers and/or sequenced in 13 mainly consanguineous, Turkish vLINCL families. Two novel, family-specific homozygous mutations were identified in the CLN6 gene. In the remaining families, all known NCL loci were excluded. To identify novel gene(s) underlying vLINCL, a genomewide single nucleotide polymorphism scan, homozygosity mapping, and positional candidate gene sequencing were performed in ten of these families. On chromosome 4q28.1-q28.2, a novel major facilitator superfamily domain containing 8 (MFSD8) gene with six family-specific homozygous mutations in vLINCL patients was identified. MFSD8 transcript was shown to be ubiquitously expressed with a complex pattern of alternative splicing. Our results suggest that MFSD8 is a novel lysosomal integral membrane protein which, as a member of the major facilitator superfamily, is predicted to function as a transporter. Identification of MFSD8 emphasizes the genetic heterogeneity of Turkish vLINCL. In families where no MFSD8 mutations were detected, additional NCL-causing genes remain to be identified. The identification of CTSD and MFSD8 increases the number of known human NCL-causing genes to eight, and is an important step towards the complete understanding of the genetic spectrum underlying NCLs. In addition, it is a starting point for dissecting the molecular mechanisms behind the associated NCLs and contributes to the challenging task of understanding the molecular pathology underlying the group of NCL disorders.

Molecular mechanisms of cancer predisposition in HNPCC/Lynch syndrome

Hereditary non-polyposis colorectal carcinoma (HNPCC; Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). It is inherited in a dominant manner with predisposing germline mutations in the MMR genes, mainly MLH1, MSH2, MSH6 and PMS2. Both copies of the MMR gene need to be inactivated for cancer development. Since Lynch syndrome family members are born with one defective copy of one of the MMR genes in their germline, they only need to acquire a so called second hit to inactivate the MMR gene. Hence, they usually develop cancer at an early age. MMR gene inactivation leads to accumulation of mutations particularly in short repeat tracts, known as microsatellites, causing microsatellite instability (MSI). MSI is the hallmark of Lynch syndrome tumors, but is present in approximately 15% of sporadic tumors as well. There are several possible mechanisms of somatic inactivation (i.e. the second hit ) of MMR genes, for instance deletion of the wild-type copy, leading to loss of heterozygosity (LOH), methylation of promoter regions necessary for gene transcription, or mitotic recombination or gene conversion. In the Lynch syndrome tumors carrying germline mutations in the MMR gene, LOH was found to be the most frequent mechanism of somatic inactivation in the present study. We also studied MLH1/MSH2 deletion carriers and found that somatic mutations identical to the ones in the germline occurred frequently in colorectal cancers and were also present in extracolonic Lynch syndrome-associated tumors. Chromosome-specific marker analysis implied that gene conversion, rather than mitotic recombination or deletion of the respective gene locus accounted for wild-type inactivation. Lynch syndrome patients are predisposed to certain types of cancers, the most common ones being colorectal, endometrial and gastric cancer. Gastric cancer and uroepithelial tumors of bladder and ureter were observed to be true Lynch syndrome tumors with MMR deficiency as the driving force of tumorigenesis. Brain tumors and kidney carcinoma, on the other hand, were mostly MSS, implying the possibility of alternative routes of tumor development. These results present possible implications in clinical cancer surveillance. In about one-third of families suspected of Lynch syndrome, mutations in MMR genes are not found, and we therefore looked for alternative mechanisms of predisposition. According to our results, large genomic deletions, mainly in MSH2, and germline epimutations in MLH1, together explain a significant fraction of point mutation-negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of Lynch syndrome families.

Function of psoriasis susceptibility gene CCHCR1

Psoriasis is a chronic skin disease characterized by abnormal keratinocyte proliferation and differentiation, neoangiogenesis and inflammation. Its etiology is multifactorial, as both the environmental and genetic factors have an important role in the pathogenesis of psoriasis. The exact disease mechanism behind psoriasis still remains unknown. The most important genetic susceptibility region for psoriasis has been located to PSORS1 locus in chromosome 6. The area includes multiply good candidate genes but the strong linkage disequilibrium between them has made genetic studies difficult. One of the candidate genes in PSORS1 is CCHCR1, which has a psoriasis-associated gene form CCHCR1*WWCC. The aim of the study was to elucidate the function of CCHCR1 and its potential role in the pathogenesis of psoriasis. In this study, transgenic mice expressing either the healthy or psoriasis-associated gene form of CCHCR1 were engineered and characterized. Mice were phenotypically normal but their gene expression profiles revealed many similarities to that observed in human psoriatic skin. In addition, the psoriasis-associated gene form had specific impacts on the expression of many genes relevant to the pathogenesis of psoriasis. We also challenged the skin of CCHCR1 transgenic mice with wounding or 12-O-tetradecanoylphorbol-13-acetate (TPA). The experiments revealed that CCHCR1 impacts on keratinocyte proliferation by limiting it. In addition, we demonstrated that CCHCR1 has a role in steroidogenesis and showed that both CCHCR1 forms promote synthesis of steroids. Also many agents relevant either for steroidogenesis or cell proliferation were shown to regulate the expression level of CCHCR1. The present study showed that CCHCR1 has functional properties relevant in the context of psoriasis. Firstly, CCHCR1 affects proliferation of keratinocytes as it may function as a negative regulator of keratinocyte proliferation. Secondly, CCHCR1 also has a role in steroidogenesis, a function relevant both in the pathogenesis of psoriasis and regulation of cell proliferation. This study suggests that aberrant function of CCHCR1 may lead to abnormal keratinocyte proliferation which is a key feature of psoriatic epidermis.