3D assessment of mandibular skeletal effects produced by the Herbst appliance.

BACKGROUND: A functional appliance is commonly used to optimize the development of the facial skeleton in the treatment of Class II malocclusion. Recent three-dimensional(3D) image-based analysis offers numerous advantages in quantitative measurement and visualization in orthodontics. The aim of this study was to localize in 3D the skeletal effect produced by the Herbst appliance on the mandible using the geometric morphometric technique. METHODS: Twenty patients treated with a Herbst appliance and subsequent fixed appliances were included. Cone-beam computed tomography (CBCT) images were taken before treatment (T1), 8 weeks after Herbst appliance removal (T2), and after subsequent fixed appliance treatment (T3). Spatially dense morphometric techniques were used to establish the corresponding points of the mandible. The mandibular morphological changes from T1-T2, T2-T3, and T1-T3 were calculated for each patient by superimposing two mandibular models at two time points with robust Procrustes superimposition. These changes were then compared to the morphological changes estimated from normative mandibular growth curves over the same period. The proportion of cases exceeding the growth expression for controls was compared to a normal population using a one tailed binomial test. RESULTS: Approximately 1.5-2 mm greater condylar changes and 0.5 mm greater changes in the chin occurred from Tl to T2. This effect lasted until the completion of treatment (T1-T3), but there was no obvious skeletal effect during the orthodontic phase (T2-T3). Approximately 40-50% of the patient sample exceeded condylar growth by > 1.5 mm compared to untreated controls (p < .05). However, changes at the chin were not statistically significant. CONCLUSIONS: The principal skeletal effect of Herbst appliance treatment was additional increase in condylar length for about half of the sample. This inconsistency may relate to the degree of mandibular growth suppression associated with a specific malocclusion.

Quantification of mandibular sexual dimorphism during adolescence.

The present study investigates how sexual dimorphism in the human mandible develops in three-dimensionally during adolescence. A cross-sectional sample of mandibular meshes of 268 males and 386 females, aged between 8.5 and 19.5 years of age, were derived from cone beam computed tomography and were analysed using geometric morphometric methods. Growth trajectories of the mandible in males and females were modelled separately using a recently developed non-linear kernel regression framework. Growth rate and direction at a dense array of points all over the mandibular surface were visualized within each group and compared between groups. We found that mandibular sexual dimorphism already exists at 9 years of age, but this is mostly in size not in shape. The differential growth rate and duration between the sexes during pubertal growth largely explained by adult sexual dimorphism: the growth direction in both males and females is similar but the male mandible changed more quickly and over a longer period than the female mandible, where the growth rate peaked and declined earlier. This results in increasing dimorphism in form, which is evident in both size and shape. The development of dimorphic features, concentrated in the chin and ramus, were further visualized. The dense morphometric approach provides detailed three-dimensional quantitative assessment of the development of sexual dimorphism of the mandible.

Three-dimensional reconstruction of Haversian systems in human cortical bone using synchrotron radiation-based micro-CT: morphology and quantification of branching and transverse connections across age.

This study uses synchrotron radiation-based micro-computed tomography (CT) scans to reconstruct three-dimensional networks of Haversian systems in human cortical bone in order to observe and analyse interconnectivity of Haversian systems and the development of total Haversian networks across different ages. A better knowledge of how Haversian systems interact with each other is essential to improve understanding of remodeling mechanisms and bone maintenance; however, previous methodological approaches (e.g. serial sections) did not reveal enough detail to follow the specific morphology of Haversian branching, for example. Accordingly, the aim of the present study was to identify the morphological diversity of branching patterns and transverse connections, and to understand how they change with age. Two types of branching morphologies were identified: lateral branching, resulting in small osteon branches bifurcating off of larger Haversian canals; and dichotomous branching, the formation of two new osteonal branches from one. The reconstructions in this study also suggest that Haversian systems frequently target previously existing systems as a path for their course, resulting in a cross-sectional morphology frequently referred to as 'type II osteons'. Transverse connections were diverse in their course from linear to oblique to curvy. Quantitative assessment of age-related trends indicates that while in younger human individuals transverse connections were most common, in older individuals more evidence of connections resulting from Haversian systems growing inside previously existing systems was found. Despite these changes in morphological characteristics, a relatively constant degree of overall interconnectivity is maintained throughout life. Altogether, the present study reveals important details about Haversian systems and their relation to each other that can be used towards a better understanding of cortical bone remodeling as well as a more accurate interpretation of morphological variants of osteons in cross-sectional microscopy. Permitting visibility of reversal lines, synchrotron radiation-based micro-CT is a valuable tool for the reconstruction of Haversian systems, and future analyses have the potential to further improve understanding of various important aspects of bone growth, maintenance and health.

Does 3D orientation account for variation in osteon morphology assessed by 2D histology?

The primary microstructural unit of cortical bone, the secondary osteon or Haversian system, is widely assumed to have a cylindrical shape. It is generally accepted that osteons are roughly circular in cross-section and deviations from circularity have been attributed to deviations from longitudinal orientation. To our knowledge this idealized geometric relationship, which assumes osteons are perfect cylinders, has not been rigorously explored. As such, we sought to explore two research questions: (i) Does the orientation of osteons in 3D explain variation in shapes visualized in 2D? (ii) Can differences in osteon 3D orientation explain previously reported age-related differences observed in their 2D cross-sectional shape (e.g. more circular shape and decreased area with age)? To address these questions we utilized a combination of 2D histology to identify osteon shape and superimposed micro-computed tomography data to assess osteon orientation in 3D based upon the osteonal canal. Shape was assessed by the inverse of Aspect Ratio (On.AspR(-1), based on a fitted ellipse) - which ranged from 0 (infinitely elongated shape) to 1 (perfectly circular). A sample (n = 27) of human female anterior femoral cortical bone samples from across the human lifespan (20-87 years) were included in the analysis, which involved 1418 osteons. The overall mean measure of On.AspR(-1) was 0.703 (1.42 Aspect Ratio). Mean osteon orientation was 79.1° (90° being longitudinal). While we anticipated a positive relation between orientation and On.AspR(-1), we found the opposite - a weak negative correlation (with more oblique 3D osteon alignment, the 2D shape became more circular as reflected by increased On.AspR(-1)). When analysis of covariance was performed with age and orientation as covariates, the negative relation with orientation was replaced by a significant relation with age alone. This relation with age accounted for 41% of the variation of On.AspR(-1). The results revealed that osteons, on average, are not circular in cross-section and that 3D orientation cannot account for deviation from circular shape. Osteons thus are strictly speaking not cylinders, as they tend to have elliptical cross-sections. We observed that osteons did become less elliptical in cross-section with age independent of orientation - suggesting this is a real change in morphology.

Normal variation in cortical osteocyte lacunar parameters in healthy young males.

The most abundant cell in bone, osteocytes form an interconnected system upon which the regulation of healthy bone relies. Although the complete nature of the role of osteocytes has yet to be defined, they are generally accepted to play a part in the sensing of load and the initiation of damage repair. A previous study conducted by our group identified variation of up to 30% in osteocyte lacunar density and morphological parameters between regions of a single cross-section of human femoral shaft; that study, however, was limited to a single individual. The aim of the current study was to determine whether this pattern consistently occurs in healthy young male femora. Anterior, posterior, medial and lateral blocks were prepared from the proximal femoral shaft of seven males and synchrotron radiation micro-CT imaged. Average lacunar densities (± SD) from the anterior, posterior, medial and lateral regions were 23 394 ± 1705, 30 180 ± 4860, 35 946 ± 5990 and 29 678 ± 6081 lacunae per mm(3) of bone tissue, respectively. These values were significantly different between the anterior and both the medial and posterior regions (P < 0.05). The density of the combined anterior and posterior regions was also significantly lower (P = 0.006) than the density of the combined medial and lateral regions. Although no difference was found in predominant orientation, shape differences were found; with the combined anterior-posterior regions having lacunae that were significantly more elongated and less flat than the combined medial-lateral values (P < 0.001). As expected, in this larger study, there was a dramatic difference in lacunar density between the medial and anterior region (up to ~ 54%). The study clearly demonstrates that the high variation seen in osteocyte lacunar density as well as other lacunar parameters, noted in a number of biomechanical, age and pathology studies, are well within the range of normal variation; however, the reasons for and consequences of this variation remain unclear. Lacunar parameters including abundance and shape are being increasingly incorporated into computational modeling of bone biology and this paper represents a more comprehensive description of normal healthy lacunae.

Femoral osteocyte lacunar density, volume and morphology in women across the lifespan.

Osteocytes are believed to be the primary agents of mechanosensing in bone. Due to this important role in the structure-function relationship of bone, osteocytes and the spaces they occupy (lacunae) are of increasing interest. Changes in lacunae with age are of particular interest in women since they are more susceptible to bone loss and fragility associated with senescent diseases including osteoporosis. This study's purpose was to test whether differences exist in lacunar density (lacunae/mm(3) of bone), orientation and morphology in the cortex of adult women spanning the human lifespan. Anterior blocks from the femoral shaft from 30 women aged 20-86years were imaged by synchrotron-radiation micro-CT. No significant relation between lacunar density and age was detected. A significant reduction in lacunar volume with age (p<0.001) was observed, alongside changes in lacunar morphology. When divided into two groups (<50 and >50years) the younger group's lacunae were ∼30% larger and were flatter (p<0.001) and less equant (spherical) (p<0.001). To our knowledge the observation that lacunar volume and morphology change over the human lifespan is novel, potentially resulting from preferential surface infilling within the extracellular space. The functional impact of this infilling is unclear but such a change in scale likely impacts the mechanosensing function of the osteocyte network. Limitations in resolution prevented us from assessing if this infilling is associated with disruption of the canaliculi. This hypothesis warrants further investigation as, if confirmed, it would represent a profound negative impact on the osteocyte network and may provide new insights into age-related bone loss.

Sexual dimorphism in multiple aspects of 3D facial symmetry and asymmetry defined by spatially dense geometric morphometrics.

Accurate measurement of facial sexual dimorphism is useful to understanding facial anatomy and specifically how faces influence, and have been influenced by, sexual selection. An important facial aspect is the display of bilateral symmetry, invoking the need to investigate aspects of symmetry and asymmetry separately when examining facial shape. Previous studies typically employed landmarks that provided only a sparse facial representation, where different landmark choices could lead to contrasting outcomes. Furthermore, sexual dimorphism is only tested as a difference of sample means, which is statistically the same as a difference in population location only. Within the framework of geometric morphometrics, we partition facial shape, represented in a spatially dense way, into patterns of symmetry and asymmetry, following a two-factor anova design. Subsequently, we investigate sexual dimorphism in symmetry and asymmetry patterns separately, and on multiple aspects, by examining (i) population location differences as well as differences in population variance-covariance; (ii) scale; and (iii) orientation. One important challenge in this approach is the proportionally high number of variables to observations necessitating the implementation of permutational and computationally feasible statistics. In a sample of gender-matched young adults (18-25 years) with self-reported European ancestry, we found greater variation in male faces than in women for all measurements. Statistically significant sexual dimorphism was found for the aspect of location in both symmetry and asymmetry (directional asymmetry), for the aspect of scale only in asymmetry (magnitude of fluctuating asymmetry) and, in contrast, for the aspect of orientation only in symmetry. Interesting interplays with hypotheses in evolutionary and developmental biology were observed, such as the selective nature of the force underpinning sexual dimorphism and the genetic independence of the structural patterns of fluctuating asymmetry. Additionally, insights into growth patterns of the soft tissue envelope of the face and underlying skull structure can also be obtained from the results.

Dysmorphometrics: the modelling of morphological abnormalities.

BACKGROUND: The study of typical morphological variations using quantitative, morphometric descriptors has always interested biologists in general. However, unusual examples of form, such as abnormalities are often encountered in biomedical sciences. Despite the long history of morphometrics, the means to identify and quantify such unusual form differences remains limited. METHODS: A theoretical concept, called dysmorphometrics, is introduced augmenting current geometric morphometrics with a focus on identifying and modelling form abnormalities. Dysmorphometrics applies the paradigm of detecting form differences as outliers compared to an appropriate norm. To achieve this, the likelihood formulation of landmark superimpositions is extended with outlier processes explicitly introducing a latent variable coding for abnormalities. A tractable solution to this augmented superimposition problem is obtained using Expectation-Maximization. The topography of detected abnormalities is encoded in a dysmorphogram. RESULTS: We demonstrate the use of dysmorphometrics to measure abrupt changes in time, asymmetry and discordancy in a set of human faces presenting with facial abnormalities. CONCLUSION: The results clearly illustrate the unique power to reveal unusual form differences given only normative data with clear applications in both biomedical practice & research.

Multiple Levels of Heuristic Reasoning Processes in Scientific Model Construction.

Science historians have recognized the importance of heuristic reasoning strategies for constructing theories, but their extent and degree of organization are still poorly understood. This paper first consolidates a set of important heuristic strategies for constructing scientific models from three books, including studies in the history of genetics and electromagnetism, and an expert think-aloud study in the field of mechanics. The books focus on qualitative reasoning strategies (processes) involved in creative model construction, scientific breakthroughs, and conceptual change. Twenty four processes are examined, most of which are field-general, but all are heuristic in not being guaranteed to work. An organizing framework is then proposed as a four-level hierarchy of nested reasoning processes and subprocesses at different size and time scales, including: Level (L4) Several longer-time-scale Major Modeling Modes, such as Model Evolution and Model Competition; the former mode utilizes: (L3) Modeling Cycle Phases of Model Generation, Evaluation, and Modification under Constraints; which can utilize: (L2) Thirteen Tactical Heuristic Processes, e.g., Analogy, Infer new model feature (e.g., by running the model), etc.; many of which selectively utilize: (L1) Grounded Imagistic Processes, namely Mental Simulations and Structural Transformations. Incomplete serial ordering in the framework gives it an intermediate degree of organization that is neither anarchistic nor fully algorithmic. Its organizational structure is hypothesized to promote a difficult balance between divergent and convergent processes as it alternates between them in modeling cycles with increasingly constrained modifications. Videotaped think-aloud protocols that include depictive gestures and other imagery indicators indicate that the processes in L1 above can be imagistic. From neurological evidence that imagery uses many of the same brain regions as actual perception and action, it is argued that these expert reasoning processes are grounded in the sense of utilizing the perceptual and motor systems, and interconnections to and possible benefits for reasoning processes at higher levels are examined. The discussion examines whether this grounding and the various forms of organization in the framework may begin to explain how processes that are only sometimes useful and not guaranteed to work can combine successfully to achieve innovative scientific model construction.

Spatially-dense 3D facial asymmetry assessment in both typical and disordered growth.

Mild facial asymmetries are common in typical growth patterns. Therefore, detection of disordered facial growth patterns in individuals characterized by asymmetries is preferably accomplished by reference to the typical variation found in the general population rather than to some ideal of perfect symmetry, which rarely exists. This presents a challenge in developing an asymmetry assessment tool that is applicable, without modification, to detect both mild and severe facial asymmetries. In this paper we use concepts from geometric morphometrics to obtain robust and spatially-dense asymmetry assessments using a superimposition protocol for comparison of a face with its mirror image. Spatially-dense localization of asymmetries was achieved using an anthropometric mask consisting of uniformly sampled quasi-landmarks that were automatically indicated on 3D facial images. Robustness, in the sense of an unbiased analysis under increasing asymmetry, was ensured by an adaptive, robust, least-squares superimposition. The degree of overall asymmetry in an individual was scored using a root-mean-squared-error, and the proportion was scored using a novel relative significant asymmetry percentage. This protocol was applied to a database of 3D facial images from 359 young healthy individuals and three individuals with disordered facial growth. Typical asymmetry statistics were derived and were mainly located on, but not limited to, the lower two-thirds of the face in males and females. The asymmetry in males was more extensive and of a greater magnitude than in females. This protocol and proposed scoring of asymmetry with accompanying reference statistics will be useful for the detection and quantification of facial asymmetry in future studies.

Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model.

BACKGROUND: The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010). METHODS: BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. RESULTS: The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone treatment induced necrotic changes in hepatic and kidney tissues. CONCLUSIONS: Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

In vitro cytotoxicity of two novel oral formulations of Amphotericin B (iCo-009 and iCo-010) against Candida albicans, human monocytic and kidney cell lines.

BACKGROUND: Invasive fungal infections such as candidiasis constitute an increasingly important medical problem. Drugs currently used for the treatment of candidiasis include polyenes (such as Amphotericin B) and azoles. Amphotericin B (AmpB) presents several limitations such as its nephrotoxicity and limited solubility. We have developed two novel lipid-based AmpB formulations which in vivo show less nephrotoxicity and enhanced solubility compared to Fungizone™ a commercial AmpB formulation. The purpose of this study was to determine the cytotoxicity of Fungizone™, Ambisome™ and two novel AmpB formulations (iCo-009 and iCo-010) against Candida albicans, human kidney (293T) cells and monocytic (THP1) cells. METHODS: Cell cytotoxicity to the AmpB formulations was evaluated by MTS and LDH assays. In vitro anti-Candida albicans activity was assessed after a 48 h drug incubation. RESULTS: None of the AmpB formulations tested showed cytotoxicity against 293T cells. In the case of THP1 cells only Fungizone™ and Ambisome™ showed cytotoxicity at 500 µg/L (n = 4-10, p < 0.05).The calculated EC50 to Candida albicans for the different formulations was as follows: 26.8 ± 2.9 for iCo-010, 74.6 ± 8.9 for iCo-009, 109 ± 31 for Ambisome™ and 87.1 ± 22 for Fungizone™ (µg of AmpB/L, n = 6-12, p < 0.05). CONCLUSIONS: The AmpB formulations analyzed were not cytotoxic to 293T cells. Cytotoxicity in THP1 cells was observed for Fungizone™ and Ambisome™, but not with the novel AmpB formulations. iCo-010 had higher efficacy compared to other three AmpB formulations in the Candida albicans model.The absence of cytotoxicity as well as its higher efficacy for the Candida model compared to Fungizone™ and Ambisome™ suggest that iCo-010 has potential in treating candidiasis.

Is bisphosphonate therapy for benign bone disease associated with impaired dental healing? A case-controlled study.

BACKGROUND: Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration) bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing. METHODS/DESIGN: A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls), matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use. DISCUSSION: This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use and osteonecrosis of the jaws.

Biodistribution and tissue toxicity of amphotericin B in mice following multiple dose administration of a novel oral lipid-based formulation (iCo-009).

OBJECTIVES: The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). METHODS: BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. RESULTS: A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. CONCLUSIONS: A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.

Visceral leishmaniasis affects liver and spleen concentrations of amphotericin B following administration to mice.

OBJECTIVES: To assess the impact of visceral leishmaniasis (VL) on the concentration of amphotericin B (AmB) recovered in the liver and spleen following either intravenous (AmBisome) or oral (iCo-009) AmB administration to mice. METHODS: Livers and spleens previously obtained from VL-infected BALB/c mice (following intravenous AmBisome or oral AmB treatments) were analysed for AmB concentrations. Then, non-infected BALB/c mice were divided into three treatment groups: a single dose of intravenous AmBisome (2 mg/kg, n = 5); and oral AmB every 12 h for 5 days (10 mg/kg, n = 6 and 20 mg/kg, n = 6). The animals were sacrificed 7 days after the initiation of the treatment and the livers and spleens were harvested for drug analysis by HPLC. RESULTS: The single intravenous injection of AmBisome resulted in a 77-fold lower concentration of AmB in infected compared with non-infected liver tissue, while the difference in AmB concentration in the spleen was only 5-fold. The multiple dose oral administration of AmB resulted in a 3-fold lower concentration of AmB in infected compared with non-infected livers for both oral doses, while the differences in AmB concentrations in the spleen were not statistically different for the oral treatment groups. CONCLUSIONS: VL significantly lowered the concentration of AmB in the liver and the spleen when compared with uninfected animals. This effect seems to correlate with the degree of infection of the tissue. In the case of the intravenous liposomal formulation (AmBisome), the differences between the infected and non-infected tissues are of a higher magnitude than in the case of orally administered AmB (iCo-009).

The use of µCT and fractal dimension for fracture prediction in osteoporotic individuals.

Osteoporosis (OP) is a widespread condition with commonly associated fracture sites at the hip, vertebra and wrist. This study examines the effects of age and osteoporosis on bone quality by comparing the efficacy of using parameters which indicate bone quality (both traditional clinical parameters such as bone mineral density (BMD), as well as apparent Young's modulus determined by finite element analysis, among others) to predict fracture. Non-fracture samples were collected from the femoral heads of 83 donors (44 males, 39 females), and fracture samples were obtained from the femoral heads of 17 donors (female). Microarchitectural parameters (Bone Volume/Total Volume [BV/TV], Bone Surface/Bone Volume [BS/BV], Tissue Mineral Density [TMD, etc.]) were measured from µCT of each sample as well as 2D and 3D fractal dimension (D2D and D3D respectively). A cube was cropped from µCT images and an isotropic hexahedral element was assigned to each voxel. Finite element analysis was used to calculate the Young's modulus for each sample. Overall, values for microarchitectural characteristics, fractal dimension measurements and Young's Modulus were consistent with values within literature. Significant correlations are observed between age and BV/TV for non-fracture males and females, as well as between age and volumetric BMD (vBMD) for the same groups. Significant differences are present between age-matched non-fracture and fracture females for BV/TV, BS/BV, vBMD, TMD, D2D, D3D, (p < 0.01 for all). Properties which are not age dependent are significantly different between age-matched non-fracture and fracture specimens, indicating OP is a disease, and not just an accelerated aging process.

Pharmacokinetics and biodistribution of amphotericin B in rats following oral administration in a novel lipid-based formulation.

OBJECTIVES: To assess the pharmacokinetics and biodistribution of amphotericin B (AmB) following oral administration in a novel mono/diglyceride-phospholipid formulation and to compare with intravenous (iv) administrations using commercial formulations. METHODS: Rats were allocated into the following treatment groups: oral gavage of AmB dispersed in mono/diglyceride-phospholipid formulation at doses of 4.5 and 10 mg/kg; iv bolus administration of 0.8 mg/kg Fungizone; iv bolus of 5 mg/kg Abelcet and iv bolus of 5 mg/kg AmBisome. Blood was sampled from jugular vein cannula at certain time points. The animals were sacrificed 72 h following administration of AmB and multiple tissues were harvested. The concentration of AmB in plasma and tissues was determined by means of HPLC. The plasma creatinine concentrations were determined using an enzymatic kit. RESULTS: The pharmacokinetics and tissue distribution of AmB following iv administrations of the commercial formulations were found to be highly formulation dependent. The terminal half-life and biodistribution of orally administered AmB in a mono/diglyceride-phospholipid formulation resembled those of Fungizone. The larger volume of the co-administered lipid-based formulation in the case of the higher dose of orally administered AmB resulted in flip-flop kinetics and in preferential distribution into the kidneys. No nephrotoxicity was detected for any formulation and route of administration. CONCLUSIONS: Oral administration of AmB in a mono/diglyceride-phospholipid formulation to rats resulted in significant intestinal absorption into the systemic circulation with pharmacokinetic and biodistribution properties similar to a micellar iv preparation.

Immediate implant placement postextraction without flap elevation.

BACKGROUND: The aim of this retrospective study was to assess soft tissue and esthetic outcomes at single-tooth immediate implants placed without flap elevation in maxillary central and lateral incisor sites. METHODS: Photographic records of 85 consecutive patients with immediate single-tooth implants in maxillary central and lateral incisors that were placed without elevation of surgical flaps were selected. The change in mucosal level was expressed as a percentage of the length of the reference central incisor. RESULTS: Significant recession of the mesial papilla (-6.2% +/- 6.8%), distal papilla (-7.4% +/- 7.5%), and facial mucosa (-4.6% +/- 6.6%) between surgical placement and 1 year was observed (P <0.001). Recession was greater for implants placed facially within the extraction socket compared to those placed lingually (P = 0.009). Sites with gingival margins initially coronal achieved mucosal levels close to the line of symmetry with the contralateral tooth. Sites initially level or apical failed to reach the line of symmetry and remained receded. For sites with initially level gingival margins, recession >10% occurred at six of 25 thin biotype sites compared to two of 19 thick biotype sites. Acceptable outcomes were achieved in the majority of sites; between 10% and 20% of sites had suboptimal esthetic results. CONCLUSIONS: Immediate implant placement without elevation of surgical flaps is associated with recession of the marginal mucosa that may fall within the threshold of visually detectable change. The orofacial position of the implant shoulder and the tissue biotype are important contributory factors.

Quantification of age-related changes in midsagittal facial profile using Fourier analysis: A longitudinal study on Japanese adult males.

OBJECTIVES: The aim of the present study was to use Fourier analysis to quantify and study age-related changes in midsagittal facial profile. MATERIALS AND METHODS: Midsagittal facial profiles were extracted as lists of x and y coordinates from 125 pairs of 3D facial scans captured at an average of 10.5 years apart for adult Japanese males aged 23-52 years. These were categorized into three 10-year-long age groups. Files of x and y coordinates underwent Fourier analysis at 30 harmonic levels. Paired t-tests were used to determine statistical significance of differences across corresponding harmonic coefficients. Mean harmonic coefficients were used to construct mean pre and post ageing profiles for each age group for qualitative comparisons. RESULTS: Full detail of facial profile was described by the first 20 harmonics. With increasing age, there was a trend of longitudinal changes involving more midsagittal shape features with increased magnitudes. However, all changes were lower than 1 mm. CONCLUSIONS: Fourier analysis is a useful morphometric approach to quantify age-related midsagittal facial changes. The small variations in the study groups prompt for testing Fourier analysis on the elderly and on other parasagittal and transverse facial features.

Marker-based watershed transform method for fully automatic mandibular segmentation from CBCT images.

OBJECTIVES:: To propose a reliable and practical method for automatically segmenting the mandible from CBCT images. METHODS:: The marker-based watershed transform is a region-growing approach that dilates or "floods" predefined markers onto a height map whose ridges denote object boundaries. We applied this method to segment the mandible from the rest of the CBCT image. The height map was generated to enhance the sharp decreases of intensity at the mandible/tissue border and suppress noise by computing the intensity gradient image of the CBCT itself. Two sets of markers, "mandible" and "background" were automatically placed inside and outside the mandible, respectively in a novel image using image registration. The watershed transform flooded the gradient image by dilating the markers simultaneously until colliding at watershed lines, estimating the mandible boundary. CBCT images of 20 adolescent subjects were chosen as test cases. Segmentation accuracy of the proposed method was evaluated by measuring overlap (Dice similarity coefficient) and boundary agreement against a well-accepted interactive segmentation method described in the literature. RESULTS:: The Dice similarity coefficient was 0.97 ± 0.01 (mean ± SD), indicating almost complete overlap between the automatically and the interactively segmented mandibles. Boundary deviations were predominantly under 1 mm for most of the mandibular surfaces. The errors were mostly from bones around partially erupted wisdom teeth, the condyles and the dental enamels, which had minimal impact on the overall morphology of the mandible. CONCLUSIONS:: The marker-based watershed transform method produces segmentation accuracy comparable to the well-accepted interactive segmentation approach.