Cephalometric studies of the mandible, its masticatory muscles and vasculature of growing Göttingen Minipigs — A comparative anatomical study to refine experimental mandibular surgery

Over many decades, the Göttingen Minipig has been used as a large animal model in experimental surgical research of the mandible. Recently several authors have raised concerns over the use of the Göttingen Minipig in this research area, observing problems with post-operative wound healing and loosening implants. To reduce these complications during and after surgery and to improve animal welfare in mandibular surgery research, the present study elucidated how comparable the mandible of minipigs is to that of humans and whether these complications could be caused by specific anatomical characteristics of the minipigs’ mandible, its masticatory muscles and associated vasculature. Twenty-two mandibular cephalometric parameters were measured on CT scans of Göttingen Minipigs aged between 12 and 21 months. Ultimately, we compared this data with human data reported in the scientific literature. In addition, image segmentation was used to determine the masticatory muscle morphology and the configuration of the mandibular blood vessels. Compared to data of humans, significant differences in the mandibular anatomy of minipigs were found. Of the 22 parameters measured only four were found to be highly comparable, whilst the others were not. The 3D examinations of the minipigs vasculature showed a very prominent deep facial vein directly medial to the mandibular ramus and potentially interfering with the sectional plane of mandibular distraction osteogenesis. Damage to this vessel could result in inaccessible bleeding. The findings of this study suggest that Göttingen Minipigs are not ideal animal models for experimental mandibular surgery research. Nevertheless if these minipigs are used the authors recommend that radiographic techniques, such as computed tomography, be used in the specific planning procedures for the mandibular surgical experiments. In addition, it is advisable to choose suitable age groups and customize implants based on the mandibular dimensions reported in this study

Structure and age-dependent development of the turkey liver: a comparative study of a highly selected meat-type and a wild-type turkey line

In this study the macroscopic and microscopic structure of the liver of a fast growing, meat-type turkey line (British United turkeys BUT Big 6, n = 25) and a wild-type turkey line (Wild Canadian turkey, n = 48) were compared at the age of 4, 8, 12, 16, and 20 wk. Because the growth plates of long bones were still detectable in the 20-week-old wild-type turkeys, indicating immaturity, a group of 8 wild-type turkeys at the age of 24 wk was included in the original scope of the study. Over the term of the study, the body and liver weights of birds from the meat-type turkey line increased at a faster rate than those of the wild-type turkey line. However, the relative liver weight of the meat-type turkeys declined (from 2.7 to 0.9%) to a greater extent than that of the wild-type turkeys (from 2.8 to 1.9%), suggesting a mismatch in development between muscle weights and liver weights of the meat-type turkeys. Signs of high levels of fat storage in the liver were detected in both lines but were greater in the wild-type turkey line, suggesting a better feed conversion by the extreme-genotype birds i.e., meat-type birds. For the first time, this study presents morphologic data on the structure and arrangement of the lymphatic tissue within the healthy turkey liver, describing two different types of lymphatic aggregations within the liver parenchyma, i.e., aggregations with and without fibrous capsules. Despite differences during development, both adult meat-type and adult wild-type turkeys had similar numbers of lymphatic aggregations

Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

BackgroundDuchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy.Methods and resultsSSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix.ConclusionsSSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy

A qualitative and quantitative macroscopic and microscopic study

The transition to using dual-purpose chickens is an alternative to killing male hatchlings of high performance egg-laying chickens. This study aimed to compare the gastrointestinal tract of a recently developed genetic line of dual purpose male chicken, Lohmann Dual (LD), with that of a broiler line, Ross 308. Eighty birds from each line were grown until they reached an average body weight 2000 g (5 weeks for Ross and 9 for LD birds). Six birds of each line were sampled weekly. Body weight (BW), normalized mass of gastrointestinal segments and relative length of intestine were determined. Histologically the villus height, epithelium height, crypt depth, mucosal enlargement factor and the tunica muscularis thickness were measured in jejunum and ileum. Data were regressed against body weight and genetic line. Jejunal enterocyte microvilli and junctional complexes length were measured. Normalized mass and relative length of the gastrointestinal segments were greater in LD birds than in Ross birds at all ages. After day 7 these decreased steadily over the lifetime of the birds in both genetic lines. The growth curves of the gastrointestinal segments of the LD birds were similar to those of the Ross birds. In birds of the same BW, LD birds had a significantly heavier gizzard, shorter intestine, higher jejunal villi, thicker ileal tunica muscularis and smaller ileal mucosal enlargement factor than were found in Ross birds. The large gizzard in LD chickens presumably increases the degree of food processing and enhances availability of nutrients in the orad part of the intestine leading to a lower nutrient concentration and a smaller absorption surface area in the ileum of the LD compared to the Ross chickens. The anatomical differences between the two lines are important criteria for further selection and should be considered in their feeding management

Basic morphometry, microcomputed tomography and mechanical evaluation of the tibiotarsal bone of a dual-purpose and a broiler chicken line

Continuous loading of the skeleton by the body’s weight is an important factor in establishing and maintaining bone morphology, architecture and strength. However, in fast-growing chickens the appendicular skeleton growth is suboptimal making these chickens predisposed to skeletal mineralization disorders and fractures. This study compared the macro- and microstructure as well as the mechanical properties of the tibiotarsus of a novel dual-purpose, Lohmann Dual (LD) and a highly developed broiler, Ross (Ross 308) chicken line. Eighty one-day-old male chicks of each line were grown until their body weight (BW) reached 2000g. Starting at the day of hatching, six birds of each line were sampled weekly. The weight, length and width of the tibiotarsus were measured and its mechanical properties (rigidity, M-Max and the M-fracture) were evaluated using the three-point bending test. Additionally, the mineral density of both, trabecular and cortical bone, the bone volume fraction, the trabecular number, thickness and separation plus cortical thickness of both chicken lines were analyzed using microcomputed tomography. The growth of the tibiotarsus in both chicken lines followed a similar pattern. At the same age, the lighter LD chickens had shorter, thinner and lighter tibiotarsi than those of Ross chickens. However, the LD chickens had a similar cortical thickness, bone volume fraction and similar mineral density of both trabecular and cortical bone to that of Ross chickens. Furthermore, the tibiotarsus of LD chickens was longer, heavier and wider than those of Ross chickens of the same BW. In addition the rigidity of the LD tibiotarsus was greater than that of Ross chickens. This suggests that the tibiotarsus of LD chickens had more bending resistance than those of Ross chickens of the same BW. Consequently, fattening LD chickens to the marketable weight should not affect their leg skeleton stability

Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease

Genome-wide association studies (GWAS) have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs) is crucial to addressing this. eQTLs vary between tissues and following in vitro cellular activation, but have not been examined in the context of human inflammatory diseases. We performed eQTL mapping in five primary immune cell types from patients with active inflammatory bowel disease (n = 91), anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 46) and healthy controls (n = 43), revealing eQTLs present only in the context of active inflammatory disease. Moreover, we show that following treatment a proportion of these eQTLs disappear. Through joint analysis of expression data from multiple cell types, we reveal that previous estimates of eQTL immune cell-type specificity are likely to have been exaggerated. Finally, by analysing gene expression data from multiple cell types, we find eQTLs not previously identified by database mining at 34 inflammatory bowel disease-associated loci. In summary, this parallel eQTL analysis in multiple leucocyte subsets from patients with active disease provides new insights into the genetic basis of immune-mediated diseases.This research was funded by a Wellcome Trust Clinical PhD Programme Fellowship (JEP), the NIH-Oxford-Cambridge Scholars Program (ACR), Wellcome Trust Grant 083650/Z/07/Z and MRC Grant MR/L19027/1 (KGCS), and the National Institute for Health Research Cambridge Biomedical Research Centre. KGCS is a National Institute for Health Research Senior Investigator. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The monoclonal antibody nBT062 conjugated to maytansinoids has potent and selective cytotoxicity against CD138 positive multiple myeloma cells _in vitro_ and _in vivo_

CD138 (Syndecan1) is highly expressed on multiple myeloma (MM) cells. In this study, we examined the anti-MM effect of murine/human chimeric CD138-specific monoclonal antibody (mAb) nBT062 conjugated with highly cytotoxic maytansinoid derivatives _in vitro_ and _in vivo_. These agents significantly inhibited growth of CD138-positive MM cell lines and primary tumor cells from MM patients, without cytotoxicity against peripheral blood mononuclear cells from healthy volunteers. In MM cells, they induced G2/M cell cycle arrest followed by apoptosis associated with cleavage of PARP and caspase-3, -8 and -9. Non-conjugated nBT062 completely blocked cytotoxicity induced by nBT062-maytansinoid conjugate, confirming that binding is required for inducing cytotoxicity. Moreover, nBT062-maytansinoid conjugates blocked adhesion of MM cells to bone marrow stromal cells (BMSCs). Co-culture of MM cells with BMSCs, which protects against dexamethasone-induced death, had no impact on the cytotoxicity of the immunoconjugates. Importantly, nBT062-SPDB-DM4 and nBT062-SPP-DM1 significantly inhibited MM tumor growth _in vivo_ in both human multiple myeloma xenograft mouse models and in SCID-human bone grafts (SCID-hu mouse model). These studies provide the preclinical framework supporting evaluation of nBT062-maytansinoid derivatives in clinical trials to improve patient outcome in MM

Advances in the treatment of monoclonal gammopaties: The emerging role of targeted therapy in plasma cell dyscrasias

The paradigm for the treatment of monoclonal gammopaties has dramatically changed: therapeutic options in multiple myeloma (MM) have evolved from the introduction of melphalan and prednisone in the 1960s, high-dose chemotherapy and stem cell transplantation in the late 1980s and 1990s, to the rapid introduction of small novel molecules within the last seven years. Based on the understanding of the complex interaction of the MM cells with the bone marrow microenvironment and the signaling pathways that are dysregulated in this process, a number of novel therapeutic agents are now available. Specifically, three novel agents with a specific-targeted anti-MM activity, have been FDA-approved for the treatment of this disease, namely Bortezomib, thalidomide, and lenalidomide which are now all playing a key role in the treatment of MM. The success of targeted therapy in MM has since led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias such as Waldenström’s macroglobulinemia and primary amyloidosis, both in the preclinical settings and as part of clinical trials

Initial Impact of Tailored Web-Based Messages about Cigarette Smoke and Breast Cancer Risk on Boys\u27 and Girls\u27 Risk Perceptions and Information Seeking: Randomized Controlled Trial

BACKGROUND: Recent evidence indicates a causal link between both active smoking and secondhand smoke (SHS) exposure and breast cancer (BC). OBJECTIVE: The objective of the present study was to evaluate the initial reactions of girls and boys to tailored Web-based messages that describe the relationship between SHS and BC, using a parallel, single-blinded cluster randomized controlled trial. METHODS: This trial was nested within a cycle of an ongoing longitudinal study of 1498 students from 74 secondary schools. Self-reported assessments were used to evaluate the impact of study messages on participants\u27 risk perception and interest in obtaining additional information after participants were randomized by schools to control or intervention groups. The intervention group received a tailored visual message (based on gender and Aboriginal status) about BC and tobacco smoke. The control group received a standard visual message about smoking and cancer. RESULTS: SHS exposure was identified as a BC risk factor by 380/1488 (25.54%) participants, during the preintervention analysis. Compared to the female participants in the control group (491/839, 58.5%), girls who received the intervention (339/649, 52.2%) were 14% more likely to agree that exposure to SHS increased their BC risk (relative risk [RR] 1.14, 95% CI 1.07-1.21). Nonsmoking girls who received the intervention were 14% more likely to agree that starting smoking would increase their BC risk (RR 1.14, 95% CI 1.07-1.21). Compared to the male participants in control group (348/839, 41.5%), boys who received the intervention (310/649, 47.8%) were 10% more likely to agree that girls\u27 exposure to SHS increased their BC risk (RR 1.10, 95% CI 1.02-1.18). Compared to controls, girls who received the intervention were 52% more likely to request additional information about SHS and BC (RR 1.52, 95% CI 1.12-2.06). CONCLUSIONS: Brief gender-sensitive messages delivered via the Internet have the potential to increase awareness and to stimulate information seeking about the risk for BC associated with SHS