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Cranial sutures are complex soft tissue structures whose mechanics are often studied due to their link with bone growth in the skull. Researchers will often use a cross-sectional two-dimensional slice to define suture geometry when studying morphometry and/or mechanical response to loading. However, using a single cross section neglects the full suture complexity and may introduce significant errors when defining their form. This study aims to determine trends in suture path variability through skull thickness in a swine model and the implications of using a 'representative' cross section on mechanical modeling. To explore these questions, a mixture of quantitative analysis of computed tomography images and finite element models was used. The linear interdigitation and width of coronal and sagittal sutures were analyzed on offset transverse planes through the skull thickness. It was found that sagittal suture width and interdigitation were largely consistent through the skull thickness, whereas the coronal suture showed significant variation in both. The finite element study found that average values of displacement and strain were similar between the two-dimensionally variable and three-dimensionally variable models. Larger ranges and more complex distributions of strain were found in the three-dimensionally variable model. Outcomes of this study indicate that the appropriateness of using a representative cross section to describe suture morphometry and predict mechanical response should depend on specific research questions and goals. Two-dimensional approximations can be sufficient for less-interdigitated sutures and when bulk site mechanics are of interest, while taking the true three-dimensional geometry into account is necessary when considering spatial variability and local mechanical response.

Masticatory muscle features allow for an understanding of how dietary habits and masticatory functions have evolved across mammalian lineages. Herbivorous mammals were traditionally classified as pertaining to either ‘ungulate-grinding’ or ‘rodent-gnawing’ morphotypes, but those classes might not adequately encompass the diversity of past and present herbivores. We compiled data for 104 herbivorous (nine orders, including new data for 31 species) and ten non-herbivorous (five orders) extant species and for four extinct taxa, in order to construct a more comprehensive scheme of masticatory morphotypes. A myological phylomorphospace revealed 15 morphotypes, which were tested statistically and interpreted morphofunctionally. Extant herbivorous morphotypes diversified along two main pathways that did not reflect the traditional types. Additionally, some extinct herbivores adapted along alternative pathways to those of extant forms. Early mammaliaforms and mammals possessed muscle proportions almost identical to those of living carnivores. Several more plesiomorphic herbivorous morphotypes were recognized, with some of them retaining generalized myological proportions. The rodent disparity was remarkable and could not be encompassed by a single category or pathway. Features of some derived euungulates and diprotodonts resembled rodents, but only a few extinct euungulates and extant wombats converged closely with them. Criteria for selecting models for palaeobiological reconstructions are discussed.

e24134 Background: Limited research suggests that war metaphors may be harmful for patients with cancer. For instance, it has been claimed that the use of war metaphors is associated with increased anxiety and depression, as well as poor coping for patients with cancer. However, little is known about how patients use and perceive these metaphors. Metaphors, which are intrinsic to the human conceptual system, help articulate patients’ experiences and needs. In this study, we explored patient narratives of illness metaphors in cancer, focusing particularly on war metaphors. Methods: Fifteen patients diagnosed with various stages of lung, colorectal or breast cancer completed semi-structured qualitative interviews about their use of metaphors after their cancer diagnoses. Interviews explored war metaphors in the context of treatment decisions, aggressiveness of care, and quality of life. Patients were also provided with a curated list of metaphors and asked about their use and experience thereof. Transcribed interviews were organized and analyzed by descriptive content analysis using NVivo software. Results: The most used metaphor categories were: 1) nature (e.g., journey, season); 2) militaristic (e.g., battle, victory, fight); and 3) uncertainty (e.g., mystery, puzzle). War metaphors were frequently referenced in patients’ support communities rather than in hospital or clinician encounters. Next, all patients with non-metastatic disease (n = 7) used war metaphors to describe their illness experience. Among all patients who used metaphorical language to describe their experience (n = 14), the only ones who did not use war metaphors (n = 2) had metastatic disease; these patients found war metaphors to be unhelpful due to their sense of having no control over the outcome. Lastly, participants reported that war metaphors served the following purposes in their illness experience with cancer: 1) promoted perseverance in the face of adversity, 2) expressed optimism, and 3) allowed them to relate cancer to previous life challenges. Conclusions: The hypothesis that war metaphors are invariably counterproductive for patients appears to be misguided. Metaphors of fighting, victory and battle worked both to empower and harm patients in this study, depending on the individual patient and their prognosis. While more prospective studies with robust sample sizes are needed to elucidate the role of metaphors in the lived experience of patients with cancer, our patients suggest the need to individualize, acknowledge and explore these metaphors for cancer populations.

Botulinum neurotoxins (BoNTs) are paralytic agents used to treat a variety of conditions in jaw muscles. Although their effect is considered temporary, there are reports of persistent functional changes. Using rabbits that received BoNT injection in one masseter muscle, the recovery of neuromuscular connection was investigated using nerve stimulation to evoke an electromyographic (EMG) response, and the recovery of muscle fibers was investigated using histological morphometry and bromodeoxyuridine (BrdU) immunohistochemistry. One month after treatment, evoked EMG was greatly reduced in both amplitude and duration, indicating that little reinnervation had taken place. Muscle fibers were atrophied and collagenous tissue was increased. Three months after treatment, evoked EMG duration was normal, indicating that at least some neuromuscular junctions were functional. Histologically, some muscle fibers were hypertrophied, some were still atrophied, and some appeared to have died. Fibrosis was still apparent amid slight increases in dividing cells and regenerating fibers. The histological effects of BoNT were evident although attenuated at a distance of about 1 cm from the injection level, but no regional differences could be discerned for the evoked EMGs. In conclusion, there were persistent muscular deficits seen 3 months after BoNT treatment that may have been caused by the failure of some affected muscle fibers to become reinnervated.

There are limited real-world data about patient-reported outcomes with immunotherapies (IO) in metastatic non-small cell lung cancer (mNSCLC). We describe patient-reported distress and clinical outcomes with IO-based treatments or cytotoxic chemotherapies (Chemo).We conducted a single-institution retrospective chart review of adults with mNSCLC treated at Duke from 03/2015 to 06/2020. At each visit, patients self-reported their distress level and sources of distress using the NCCN Distress Thermometer (DT) and its 39-item Problem List. We abstracted demographic, clinical, distress, and investigator assessed-clinical response data, then analyzed these using descriptive statistics and generalized estimating equations.Data from 152 patients were analyzed in four groups: Chemo alone, IO + Chemo, single agent IO, dual agent IO. Distress was worse before treatment start in all groups, and the odds of actionable distress (DT score 4) decreased by 10 % per month. The most frequent sources of distress were physical symptoms (e.g., fatigue, pain), which remained high longitudinally. Patients receiving IO had higher clinical response rates and a lower rate of unplanned healthcare encounters compared to patients treated with Chemo alone. Only one-third of all patients were seen by palliative care.This single-center, real-world evidence study demonstrates that patients with mNSCLC experience significant distress prior to starting first-line treatment. IO treatment was associated with higher clinical benefit rates and lower healthcare utilization compared to chemotherapy. Symptom distress persists over time, highlighting potential unmet palliative and supportive care needs in mNSCLC care in the IO treatment era.

Objective To evaluate cone-beam computed tomography (CBCT) image quality via cephalometric measurement variability while reducing radiation exposure by altering the radiographic technique. Materials and Methods A human cadaver was imaged using a Morita Accuitomo 170 CBCT machine at various technique parameters: tube voltages of 60, 70, 80, and 90 kV, tube currents of 1, 2.5, and 5 mA, and rotational arcs of 180° and 360°. From the rotation data, standard cephalogram views were generated. Point radiation dose measurements were recorded at the entry of three key radiosensitive regions. Ten examiners measured seven cephalometric parameters on the conventional cephalogram and each derived view. Measurement error and dose were compared between radiographic techniques and a standard cephalometric procedure. Results Generally insignificant differences in measurement error were observed when rotation arc was reduced from 360° to 180°, when tube current was reduced from 5 mA to 2.5 mA, and when tube voltage was reduced from 90 kV to 80 kV and 70 kV. Radiation dose could be halved for either of the rotation arc or tube current reductions; reducing both yielded dose comparable to standard cephalometric imaging. Using 1 mA or 60 kV rendered nondiagnostic images. Discussion The study's cadaver included embalming fluid, a lack of patient-motion-induced image blur, and lesser bone density relative to a typical adolescent orthodontic patient, which can yield images not wholly representative of live patients. Conclusion Orthodontists could image with CBCT using a 180° arc of rotation, 2.5 mA, and 70 or 80 kV to reduce radiation dose while yielding images of adequate quality that are derived from three-dimensional data.

Botulinum neurotoxins (BoNT) are used in masticatory muscles for pain relief, unloading of the mandible, and cosmetic facial contouring. Treatment is often repeated every few months as function returns. This study assessed masticatory function and musculoskeletal structure after multiple BoNT treatment of the rabbit masseter.Female rabbits received 3 injections of BoNT (n = 13) or saline (n = 5) into one masseter muscle at intervals of 12 weeks. The contralateral side served as control. Periodic measurements of masticatory electromyography (EMG) and stimulated anterior bite force were made. After the final 12-week recovery interval, neuromuscular connection was investigated by stimulating the masseteric nerve to elicit an evoked EMG response. Mandibular specimens were collected for microCT analysis, and masseters were collected for histomorphometry and counts of replicating cells.Control and saline-injected muscles maintained consistent masticatory EMG and anterior bite force throughout the study. BoNT-injected masseters showed strong declines after each injection; during the 12-week recovery period, masticatory EMG and anterior bite force improved, although only electrical activity reached normal levels. Multiple injection resulted in persistently atrophied muscle fibers with fibrosis, and notable loss of bone from the mandibular body and condyle. The uninjected masseters of the BoNT group also showed evidence of mild toxin-related changes.Although muscle function is mostly regained after each injection, masseters receiving multiple doses of BoNT show extensive damage. In addition, mandibular bone density is decreased on the injected side.

Cancer patients' sources of distress are often unaddressed, and patient-reported distress data could be utilized to identify those with unmet and impending care needs. We explored the association between moderate/severe distress and healthcare utilization in a large sample of non-small cell lung cancer (NSCLC) and non-colorectal gastrointestinal cancer patients.Adult patients treated between July 2013 and March 2019. Data from the NCCN Distress Thermometer (DT) and the accompanying "Problem List" were extracted from the EHR. A DT score of ≥ 4 indicates "actionable distress." Statistical analysis was performed using descriptive analysis for patient characteristics, clinical outcomes, and sources of distress. Generalized linear mixed models were fit to determine the relationship between distress and healthcare utilization (hospitalization, emergency department (ED) visit, or both).The ten most frequently reported problems were from the Physical and Emotional domains of the Problem List. Distress was mostly related to physical symptoms (pain, fatigue) and emotional issues (worry, fears, sadness, nervousness). Patients with actionable distress generally reported more problems across all their visits. Actionable distress was associated with higher odds of the composite outcome measure of hospitalization or visiting the ED, within both the next 3 months (OR = 1.37; 95% CI = 1.19, 1.58; p 0.001) and 6 months (OR = 1.19; 95% CI = 1.03, 1.37; p = 0.019).Patients with significant distress had marked utilization of ED and inpatient services. DT scores are a source of untapped data in the EHR that can highlight patients in need of intervention, including palliative care and cancer support services.

e24138 Background: Distress has a negative impact on the patient experience of cancer. We previously demonstrated that patients with metastatic non-small cell lung cancer (mNSCLC) face significant and sustained distress during first-line treatment. However, the association between distress and unplanned healthcare utilization (HCRU) is not well understood. Here we examine this association. Methods: We conducted secondary analyses of data from 152 adult patients with mNSCLC treated at Duke Cancer Institute who were part of a retrospective chart review study (3/15-6/20). For the original investigation, demographic, clinical, and distress data were abstracted. NCCN Distress Thermometer (DT) scores were recorded at each clinic visit from start of first-line therapy to end of first year, change in therapy or death. The DT is an 11-point ordinal scale, with a 39-item Problem List, assessing overall distress. DT scores of > = 4 indicate actionable distress. Further HCRU data were analyzed, including unplanned hospitalizations, 30-day readmissions, length of stay, clinic visits, infusion center visits, emergency department (ED) visits, and death. Descriptive statistical analyses were performed for sources of distress and HCRU. To examine the association between distress and HCRU, we utilized an adjusted frailty model (for baseline demographics, metastatic site, and National Cancer Institute Index). This Cox proportional hazards model allowed for multiple HCRU events per patient and included actionable distress as a time-dependent covariate. Results: First, the proportion of actionable DT scores (423/1652, 25.6%) was strikingly high. Most DTs included report of at least one physical problem (n = 1593, 96.4%), regardless of distress level. However, emotional problems (e.g., worry, nervousness, depression) were reported much more frequently when the DT score was actionable (61.9% vs. 20.8%). At the patient level (n = 152), actionable distress was associated with increased HCRU. For example, a larger proportion of those with an average DT score > = 4 had at least one hospitalization (n = 22, 53.7%), infusion center visit (n = 11, 26.8%) or ED visit (n = 28, 68.3%) compared to patients with a non-actionable average DT score. Furthermore, HCRU was 54% more likely to occur after a patient reporting actionable distress compared to a patient reporting lower distress levels any time during treatment (adjusted HR 1.54; CI 1.20, 1.97). A one-point increase in distress was associated with an 8% increase in risk of HCRU (HR 1.08; CI 1.03, 1.13) at any point during treatment. Conclusions: Patients with mNSCLC experience high levels of distress, with actionable distress appearing to be driven significantly by emotional problems. Patient-reported distress is also associated with HCRU. Intervention development and testing is needed to address the unmet psychological needs in lung cancer care and their potential impact on unplanned HCRU.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by a poor prognosis but also a paradoxical possibility of cure. This renders decision-making complex and imminent. Unfortunately, many patients with AML misestimate their prognosis and treatment risk. While decision aids can improve illness understanding and reduce decisional conflict, there are no validated decision aids for AML. We developed and tested a novel AML decision aid (NCT03442452).Patients (n = 20) were recruited at Duke University from May 2018 to February 2019. Participants completed assessments of AML knowledge and decisional conflict, before and after using the electronic decision aid. The primary endpoint was feasibility (endpoint met if80% of study participants completed all study components). Secondary analyses of efficacy were conducted using paired t tests for dependent pre-/post-samples.The primary endpoint of feasibility was met (100% of participants completed all study components). Secondary analyses showed improved knowledge and reduced decisional conflict after using the decision aid. Knowledge scores improved from a mean of 11.8 (out of 18) correct items at baseline to 15.1 correct items after using the decision aid (mean difference 3.35; p0.0001). Decisional conflict scores reduced significantly from baseline to post-test as well (mean difference - 6.5; p = 0.02).These findings suggest that our AML decision aid is a useful tool to improve the patient experience and promote shared decision-making in AML. A randomized efficacy trial is planned.

The development of the mandibular symphysis in late fetal and postnatal pigs, Sus scrofa dom. (n = 17), was studied as a model for the early fusing symphysis of anthropoid primates, including humans. The suture-like ligaments occurring in species that retain a mobile symphysis are not present in the pig. Instead, cartilage is the predominant tissue in the mandibular symphysis prior to fusion. In late fetuses the rostrum of the fused Meckel's cartilages forms a minor posterior component of the symphysis whereas the major component is secondary cartilage, developing bilaterally and joined at the midline with mesenchyme. This remnant of Meckel's cartilage likely fuses with the flanking secondary cartilage. The overall composition of pig symphyseal histology in fetal and infant animals varies regionally and individually. Regions where the paired secondary cartilages abut in the midline resemble double growth plates. Chondrogenic growth in width of the symphysis is likely important in early stages, and central proliferation of mesenchyme is the probable source of new chondrocytes. Laterally, the chondrocytes hypertrophy near the bone fronts and are replaced by alveolar bone. Complete synostosis except for a small cartilage remnant had occurred in one 8-week-old postnatal specimen and all older specimens. Surprisingly, however, the initial phase of symphyseal fusion, observed in a 5-week-old postnatal specimen, involved intramembranous ossification of midline mesenchyme rather than endochondral ossification. Subsequently, fusion progresses rapidly at the anterior and labial aspects of the symphysis, leaving only a small postero-lingual cartilage pad that persists for at least several months. Anat Rec, 302:1372-1388, 2019. © 2018 Wiley Periodicals, Inc.

In addition to conveying the forces of attaching muscles and ligaments to the zygomatic and temporal bones, the arch periosteum is responsible for lateral apposition and medial resorption during the growth period. In this contribution, we describe the vasculature of the zygomatic arch in young pigs (Sus scrofa dom.) in order to understand the relationship of osseous and periosteal vessels to each other, to surrounding tissues, and to patterns of modeling. Subjects 2–6 weeks of age were perfused with vascular fill; some also received the vital bone label calcein. Whole mounts were prepared of the decalcified bony arch and of its lateral periosteum. Undecalcified arches were plastic-embedded and thick-sectioned. Additional observations on cell replication were made using material from a previous study. The osseous and periosteal vascular supplies were largely independent, joined only by a fine network at the tissue interface. Osseous vessels entered the medial side of the arch through clusters of nutrient foramina. The intraosseous branching pattern resembled the direction of appositional growth, which in turn describes the disposition of bony trabeculae in older pigs. In contrast, vessels arrived at the periosteum via muscles and ligaments and thus its perfusion may partially depend on functional activity. The open weave of periosteal vessels bore little similarity to bone architecture, especially for the temporal bone, but the appositional lateral periosteum showed indications of angiogenesis, whereas the thinner, resorptive periosteum on the medial side featured composite, possibly fusing vessels at the bone surface. Anat Rec, 299:1661–1670, 2016. © 2016 Wiley Periodicals, Inc.

Mobility is a fundamental characteristic of mammalian teeth, and has been widely used to determine individual tooth prognosis. However, the direction and extent of tooth movement under functional loads are unknown. This study investigated maxillary molar mobility, alveolar bending, and periodontal space (PDL) fluid pressure during mastication and masseter muscle contraction in young pigs, along with PDL space measurements. Twelve three-month-old farm pigs were instrumented with some or all of the following: (1) ultrasonic crystals, one implanted into the pulp chamber of a deciduous maxillary molar and additional crystals glued onto its buccal and palatal alveolar plates; (2) rosette strain gauges affixed to the buccal and palatal of alveolar ridges; (3) a pressure transducer inserted into palatal alveolar bone facing the PDL. Tooth mobility, alveolar bending, and fluid pressure were simultaneously recorded during unrestrained feeding and subsequent masseter muscle stimulation. The PDL widths were measured using micro-CT. The results indicate that during the power stroke of mastication, (1) the molar displaced buccally and apically (192 ± 95 µm) regardless of the side of chewing; (2) compressive bone strain was greater on the buccal than on the palatal alveolar plate; and (3) PDL pressure increased during the power strok (3.63 ± 0.80 kPa). Masseter contraction produced similar results but with generally lower values. The PDL widths were larger than the range of tooth mobility, and showed no correlation with the mobility. Thus occlusal function causes buccal tipping and intrusion of maxillary molars with concomitant compression of the buccal alveolar plate and raised pressure within the PDL space.

OBJECTIVE: To compare the morphology and mechanical function of sutures in normal pigs and minipigs to those of Yucatan minipigs, a natural model for midfacial hypoplasia. SETTING AND SAMPLE POPULATION: Research took place at the Department of Orthodontics at the University of Washington and used varying sample sizes of normal-snouted pigs and Yucatan minipigs. MATERIAL AND METHODS: Skulls and heads were examined for morphology of the nasofrontal suture using computed tomography and histology. Strain gauge recordings were made of sutural strain during mastication and during cyclic tensile loading of the nasofrontal suture. RESULTS: Sutures in Yucatans had narrower gaps than same-age normal pigs. The nasofrontal suture was simpler in construction and had more active osteoblasts on the bone fronts in Yucatans. The sutural ligament was less well organized, and based on a small sample, masticatory strain appeared to be lower than in normal minipigs. However, sutures were not fused and showed similar strains in response to the cyclic loading procedure. CONCLUSION: Midfacial hypoplasia in Yucatan pigs has the likely proximate cause of hyperossification. Yet prior to fusion, the sutures appear to be amenable to treatment that would promote their growth rate.

During early stages of postnatal development, pressure from the growing brain as well as cerebrospinal fluid, i.e. intracranial pressure (ICP), load the calvarial bones. It is likely that such loading contributes to the peripheral bone formation at the sutural edges of calvarial bones, especially shortly after birth when the brain is growing rapidly. The aim of this study was to quantify ICP during mouse development. A custom pressure monitoring system was developed and calibrated. It was then used to measure ICP in a total of seventy three wild type mice at postnatal (P) day 3, 10, 20, 31 and 70. Retrospectively, the sample in each age group with the closest ICP to the average value was scanned using micro-computed tomography to estimate cranial growth. ICP increased from 1.33±0.87mmHg at P3 to 1.92±0.78mmHg at P10 and 3.60±1.08mmHg at P20. In older animals, ICP plateaued at about 4mmHg. There were statistically significant differences between the ICP at the P3 vs. P20, and P10 vs. P20. In the samples that were scanned, intracranial volume and skull length followed a similar pattern of increase up to P20 and then plateaued at older ages. These data are consistent with the possibility of ICP being a contributing factor to bone formation at the sutures during early stages of development. The data can be further used for development and validation of computational models of skull growth.

Introduction Temporary paralysis of the masseter muscle caused by botulinum toxin is a common treatment for temporomandibular disorders, bruxism, and muscle hypertrophy. Loss of masseter force is associated with decreased mandibular mineral density. Our objectives were (1) to establish whether bone loss at the mandibular condyle is regionally specific and (2) to ascertain whether the treatment affects the condylar cartilage. Methods Young adult female rabbits received a unilateral masseter injection of botulinum neurotoxin serotype A (BoNT/A, n = 31), saline solution (n = 19), or no injection (n = 3) and were also injected with bromodeoxyuridine (BrdU), a replication marker. The rabbits were killed at 4 or 12 weeks after treatment. The condyles were processed for paraffin histology. Cortical thickness, cartilage thickness, and trabecular bone areal density were measured, and replicating cells were counted after BrdU reaction. Results The BoNT/A rabbits exhibited a high frequency of defects in the condylar bone surface, occurring equally on the injected and uninjected sides. Bone loss was seen only on the side of the BoNT/A injection. Cortical as well as trabecular bone was severely affected. The midcondylar region lost the most bone. Recovery at 12 weeks was insignificant. Condylar cartilage thickness showed no treatment effect but did increase with time. The numbers of proliferating cells were similar in the treatment groups, but the BoNT/A animals showed more side asymmetry associated with the condylar defects. Conclusions Bone loss may be a risk factor for the use of botulinum toxin in jaw muscles.

Introduction Current craniofacial growth modification devices use static forces, but cyclic forces are believed by some to be more effective. The latter have not been evaluated in large animal models, and it is not known how such forces are transmitted to distant parts of the skull. In this study, we aimed to (1) develop a portable loading system capable of delivering reliable cyclic loads to the porcine nasofrontal suture (NFS), (2) explore strain transmission to distant sutures, and (3) characterize the sutural growth effects in a small pilot study. Methods After we validated the device, cyclic (2.5 Hz) tensile loads were applied unilaterally to the NFS of 6 abattoir pig heads, with strain gauges on multiple sutures. Similar loading was applied to 3-month-old live pigs (Sus scrofa, n = 4 and 1 sham) 30 minutes per day for 5 days. These animals received fluorescent markers of mineralization on loading days 1 and 3. Suture strains were recorded on day 5. Histomorphometric analysis quantified suture width and mineral apposition rate. Results A wearable loading system was developed to produce an average of +900 microstrain at the targeted NFS. Substantial strains were seen at the contralateral NFS and midline sutures, but bone strains were low. Strain patterns were similar ex vivo and in vivo, with the latter generally having higher magnitudes. Preliminary evidence demonstrates wider sutures with higher mineral apposition rates in the loaded sutures. Conclusions Daily spurts of cyclic load caused sutural strain throughout the skull. This regimen most likely enhances sutural growth and may be therapeutically useful.

The growth of the nasal septal cartilage is believed to be a driving force of midfacial growth. Cellular proliferation is an important contributor to growth of the cartilage, but this factor has been rarely investigated. The current study was undertaken to assess the proliferation and cellular density in the septal cartilage of fast-growing juvenile minipigs. Six minipigs averaging 4.4 ± 1 months old were injected with 5'-bromo-2'-deoxyuridine (BrdU), a thymidine analog, 24 h before death. The septal cartilage was sectioned in the coronal plane and reacted for BrdU. The proliferative index (number of BrdU-positive chondrocytes/total number of chondrocytes) and cellular density (number of cells mm(-2) ) of various locations of the septum were measured and compared in order to determine overall proliferation rate and whether regional variations in proliferative activity and cellular density are present. To provide a time perspective to the problem of midfacial growth, the lengths of the nasal bone and the palate were measured in a collection of 61 dry skulls of minipigs aged 1-8 months. Results showed that the septal chondrocytes were proliferating at a surprisingly high rate (~21%). The proliferative index was higher in the ventral and middle compared with the dorsal locations, and in the central cartilage compared with the perichondrium. No difference in proliferative index was found between the anterior and posterior parts of the septum. Cellular density was higher in the perichondrium than in the central cartilage. Within the central cartilage there was a trend for higher cellular density anteriorly. In conclusion, the rapidly growing midface of juvenile minipigs is associated with a high rate of septal proliferation, especially in the ventral half of the cartilage.

In this study, the virus-removal capacity of nanofiltration was assessed using validated laboratory scale models on a wide range of viruses (pseudorabies virus; human immunodeficiency virus; bovine viral diarrhea virus; West Nile virus; hepatitis A virus; murine encephalomyocarditis virus; and porcine parvovirus) with sizes from 18 nm to 200 nm and applying the different process conditions existing in a number of Grifols' plasma-derived manufacturing processes (thrombin, α1-proteinase inhibitor, Factor IX, antithrombin, plasmin, intravenous immunoglobulin, and fibrinogen). Spiking experiments (n = 133) were performed in process intermediate products, and removal was subsequently determined by infectivity titration. Reduction Factor (RF) was calculated by comparing the virus load before and after nanofiltration under each product purification condition. In all experiments, the RFs were close to or greater than 4 log10 (>99.99% of virus elimination). RF values were not significantly affected by the process conditions within the limits assayed (pH, ionic strength, temperature, filtration ratio, and protein concentration). The virus-removal capacity of nanofiltration correlated only with the size of the removed agent. In conclusion, nanofiltration, as used in the manufacturing of several Grifols' products, is consistent, robust, and not significantly affected by process conditions.

Introduction The nasal septum is thought to be a primary growth cartilage for the midface and, as such, has been implicated in syndromes involving midfacial hypoplasia. However, this internal structure is difficult to study directly. The aims of this study were to provide direct, continuous measurements of the growth of the nasal septal cartilage and to compare these with similar measurements of the nasofrontal suture to test whether the growth of the cartilage precedes the growth of the suture and whether the growth of the septal cartilage is constant or episodic. Methods Ten Hanford minipigs were used. Linear displacement transducers were implanted surgically in the septal cartilage and across the nasofrontal suture. Length measurements of the cartilage and suture were recorded telemetrically each minute for several days. Results The growth rate of the nasal septal cartilage (0.07% ± 0.03% length/h) was significantly higher than that of the suture (0.03% ± 0.02% length/h) (P = 0.004). The growth of both structures was episodic with alternating periods of growth (5-6 per day) and periods of stasis or shrinkage. No diurnal variation in growth of the cartilage was detected. Conclusions These results are consistent with the notion that growth of the septal cartilage might drive growth of the nasofrontal suture. Growth of the midface is episodic rather than constant.

Nanofiltration assures that protein therapeutics are free of adventitious agents such as viruses. Nanofilter pores must allow passage of protein drugs but be small enough to retain viruses. Five nanofilters have been evaluated to identify those that can be used interchangeably to yield a high purity Coagulation Factor IX product. When product preparations prior to nanofiltration were analyzed using electrophoresis, Western blot, liquid chromatography - tandem mass spectrometry and size exclusion HPLC, factor IX, inter - α - trypsin inhibitor and C4b binding protein (C4BP) were observed. C4BP was removed from product by all five nanofilters when nanofiltration was performed at physiological ionic strength. However, at high ionic strength, C4BP was removed by only two nanofilters. HPLC indicated that the Stokes radius of C4BP was larger at low ionic strength than at high ionic strength. The results suggest that C4BP exists in an open conformation at physiological ionic strength and is removed by nanofiltration whereas, at high ionic strength, the protein collapses to an extent that allows passage through some nanofilters. Manufacturers should be aware that protein contaminants in other nanofiltered protein drugs could behave similarly and conditions of nanofiltration must be evaluated to ensure consistent product purity.

The size and the shape of craniofacial bones results from periosteal activity, which can be either appositional or resorptive. The periosteum is often used as a source of graft material for osteogenesis, but differences in cellular makeup and proliferative capacity may render resorptive regions unsuitable for transplant. This study was undertaken to characterize the cells in appositional and resorptive periosteum, and to assess variation in proliferative activity. Young pigs (n = 9) were injected with bromodeoxyuridine to label replicating cells and killed 3 h later. The mandibular ramus, hard palate and zygomatic arch were examined for patterns of periosteal activity, and replicating cells were quantified in 16 appositional and eight resorptive regions. Sections were also reacted for markers of osteogenic (Runx2) and osteoclastic [CTR (calcitonin receptor), RANK, TRAP, CD14] lineage, and for an endothelial label (lectin). Replicating cells were often associated with the vasculature; most were unreactive for markers of differentiation. Although the fibrous layers of periosteum had fewer replicating cells per unit area than inner layers (P

The buccinator muscle forms the lateral wall of the oral cavity. It is presumed to aid mastication by maintaining bolus position. Such a function would involve thickening the cheek, possibly compressing the alveolar bone and contributing to malocclusions. However, neither buccinator deformation nor its effect on pressure has been demonstrated. Our objective was to evaluate buccinator EMG during feeding, its changes in length and thickness, and the pressure exerted on its alveolar attachment, using miniature pigs as an animal model.EMG of the buccinator and other oral muscles was recorded with fine-wire electrodes. Anteroposterior length and mediolateral thickness of the buccinator were evaluated with implanted sonomicrometry crystals, and pressure was measured by flat transducers placed beneath the mandibular origin of the buccinator. Recordings were made during feeding and muscle stimulation. Tissues were collected postmortem for histology.During mastication, buccinator EMG showed regular peaks that preceded those of the jaw closers. Pattern differences clearly distinguished working and balancing sides. The buccinator shortened and thickened when it contracted. Positive pressures were observed at the mandibular attachment of the buccinator, increasing when the muscle was active. Histological evaluation showed a complex interweaving of fibres closely associated with salivary tissue.Buccinator contraction does thicken the cheek, and during mastication this activity takes place just as the closing stroke begins. In addition to controlling the bolus, there may be an effect on salivation. Despite the fact that the muscle pulls on its attachment, the local mechanical environment at the alveolar bone is one of positive pressure.

Non-healing fractures can result from trauma, disease, or age-related bone loss. While many treatments focus on restoring bone volume, few try to recapitulate bone organization. However, the native architecture of bone is optimized to provide its necessary mechanical properties. Hyaluronic acid (HA) hydrogel scaffold systems with tunable degradation properties were developed for the controlled delivery of osteoinductive and angiogenic growth factors, thus affecting the quantity and quality of regenerated tissue. HA hydrogels were designed to degrade at fast, intermediate, and slow rates due to hydrolysis and further provided controlled release of cationic proteins due to electrostatic interactions. Scaffolds delivering bone morphogenetic protein-2 (BMP-2) were evaluated in a rat calvarial bone critical size defect model. BMP-2 delivery from the HA hydrogels had a clear osteoinductive effect in vivo and, for all hydrogel types, BMP-2 delivery resulted in significant mineralization compared to control hydrogels. The temporal progression of this effect could be modulated by altering the degradation rate of the scaffold. All three degradation rates tested resulted in similar amounts of mineral formation at the latest (six week) time point examined. Interestingly, however, the fastest and slowest degrading scaffolds seemed to result in more organized bone than the intermediate degrading scaffold, which was designed to degrade in 6–8 weeks to match the healing time. Additionally, healing could be enhanced by co-delivery of vascular endothelial growth factor along with BMP-2.

Gordon E Anderson was born in Aberdeen, the son of a medical biochemist at the Victoria Infirmary, Glasgow. He was initially schooled in Glasgow but returned to Aberdeen Grammar School as a boarder, during which time he developed an interest in engineering. At 18 he was diagnosed with tuberculosis, and during treatment he reconsidered his career plans. Excluded from national service he applied, successfully, for a place to read medicine at Glasgow Medical College. He graduated in 1964. He started his specialist training in on obstetrics and gynaecology at Queen Mary’s Hospital in Glasgow under …

Objectives The purpose of this study was to investigate the effects of reduced masticatory function on midline suture growth and morphology in growing pigs.

Objective Loading of temporomandibular tissues during mandibular distraction may cause changes in condylar growth and cartilage thickness. This study examines the effects of distraction on the condyle in a large animal model by explicitly measuring growth and in vivo loading. Design Unilateral mandibular distraction was carried out on 20 growing minipigs divided into three groups. One group underwent distraction but not consolidation, whereas the other two groups were allowed a period of consolidation of either 1 or 2 weeks. Animals received fluorochrome and 5-bromo-2′-deoxyuridine (BrdU) labelling and masticatory strain was measured from the condylar neck. Condylar strain was also recorded in an age-matched sample of eight animals that received no distraction surgery. Immunohistochemical procedures were used to identify dividing prechondroblasts and histological analysis was used to measure mineral apposition rate, count dividing cells, and measure the thickness of condylar cartilage. Results Strain magnitude, particularly compressive strain, was much larger on the non-distraction side compared to the distraction side condyle. Compared to normal loading levels, the distraction side condyle was underloaded whereas the condyle on the intact side was overloaded. Mineral apposition and cartilage thickness were greater on the distraction side condyle compared to the opposite side. Differences between the sides were most pronounced in the group with no consolidation and became progressively reduced with consolidation time. Conclusions Increased mineralisation and cartilage thickness on the distraction side condyle are associated with reduced, not increased loading, perhaps because of disruption of the distraction side masseter muscle.

Bone growth at the cranial sutures relies on proliferation of osteogenic progenitor cells and/or differentiation of osteoblasts. The current study was undertaken to assess these events in relation to suture growth and fusion. A total of 21 pigs, divided into three age groups (0.5–1.5 months, 3–4 months and 5–7 months), were used for immunohistochemical evaluation of cell proliferation (BrdU) and osteogenic differentiation (Cbfa1/Runx2) in the interfrontal and interparietal sutures. Proliferation and osteogenic differentiation were both more prominent near the bone fronts than in the central zone. With age, both proliferation and osteogenic differentiation diminished. Proliferation ceased on the endocranial (dura mater) side by the age of 3–4 months. Proliferation on the pericranial side was accompanied by active bone formation and initiation of suture fusion from this side. In conclusion, (1) decreased suture bone growth with age reflects decreased cell proliferation and probably also osteogenic differentiation, and (2) suture fusion occurs from the pericranial side where activity remains relatively high.

SUMMARY Modulation of force during mammalian mastication provides insight into force modulation in rhythmic, cyclic behaviors. This study uses in vivo bone strain data from the mandibular corpus to test two hypotheses regarding bite force modulation during rhythmic mastication in mammals: (1)that bite force is modulated by varying the duration of force production, or(2) that bite force is modulated by varying the rate at which force is produced. The data sample consists of rosette strain data from 40 experiments on 11 species of mammals, including six primate genera and four nonprimate species: goats, pigs, horses and alpacas. Bivariate correlation and multiple regression methods are used to assess relationships between maximum(ϵ1) and minimum (ϵ2) principal strain magnitudes and the following variables: loading time and mean loading rate from 5% of peak to peak strain, unloading time and mean unloading rate from peak to 5% of peak strain, chew cycle duration, and chew duty factor. Bivariate correlations reveal that in the majority of experiments strain magnitudes are significantly (P

The nasofrontal suture links the nasal complex with the braincase and is subject to compressive strain during mastication and (theoretically) tensile strain during growth of nasal soft tissues. The suture’s ability to transmit compressive and tensile loads therefore affects both cranioskeletal stress distribution and growth. This study investigated the in vitro viscoelastic and failure properties of the nasofrontal suture in the pig, Sus scrofa. Suture specimens from two ages were tested in compression and tension and at fast and slow rates. In additional specimens, strain gauges were applied to the suture and nasal bone for strain measurement during testing. Relaxation testing demonstrated higher elastic moduli in tension than compression, regardless of test rate or pig age. In contrast, maximum elastic moduli from failure tests, as well as peak stresses, were significantly higher in compression than in tension. Sutures from older pigs tended to have higher elastic moduli and peak stresses, significantly so for tensile relaxation moduli. Strain gauge results showed that deformation at the suture was much greater than that of the nasal bone. These data demonstrate the viscoelasticity and deformability of the nasofrontal sutural ligament. The suture achieved maximal resistance to tensile deformation at low loads, corresponding with the low tensile loads likely to occur during growth of nasal soft tissues. In contrast, the maximal stiffness in compression at high loads indicates that the suture functions with a substantial safety factor during mastication.