Beyond bone volume: Understanding tissue-level quality in healing of maxillary vs. femoral defects.

Currently, principles of tissue engineering and implantology are uniformly applied to all bone sites, disregarding inherent differences in collagen, mineral composition, and healing rates between craniofacial and long bones. These differences could potentially influence bone quality during the healing process. Evaluating bone quality during healing is crucial for understanding local mechanical properties in regeneration and implant osseointegration. However, site-specific changes in bone quality during healing remain poorly understood. In this study, we assessed newly formed bone quality in sub-critical defects in the maxilla and femur, while impairing collagen cross-linking using ß-aminopropionitrile (BAPN). Our findings revealed that femoral healing bone exhibited a 73 % increase in bone volume but showed significantly greater viscoelastic and collagen changes compared to surrounding bone, leading to increased deformation during long-term loading and poorer bone quality in early healing. In contrast, the healing maxilla maintained equivalent hardness and viscoelastic constants compared to surrounding bone, with minimal new bone formation and consistent bone quality. However, BAPN-impaired collagen cross-linking induced viscoelastic changes in the healing maxilla, with no further changes observed in the femur. These results challenge the conventional belief that increased bone volume correlates with enhanced tissue-level bone quality, providing crucial insights for tissue engineering and site-specific implant strategies. The observed differences in bone quality between sites underscore the need for a nuanced approach in assessing the success of regeneration and implant designs and emphasize the importance of exploring site-specific tissue engineering interventions. STATEMENT OF SIGNIFICANCE: Accurate measurement of bone quality is crucial for tissue engineering and implant therapies. Bone quality varies between craniofacial and long bones, yet it's often overlooked in the healing process. Our study is the first to comprehensively analyze bone quality during healing in both the maxilla and femur. Surprisingly, despite significant volume increase, femur healing bone had poorer quality compared to the surrounding bone. Conversely, maxilla healing bone maintained consistent quality despite minimal bone formation. Impaired collagen diminished maxillary healing bone quality, but had no further effect on femur bone quality. These findings challenge the notion that more bone volume equals better quality, offering insights for improving tissue engineering and implant strategies for different bone sites.

The prevalence of gambling and problematic gambling: a systematic review and meta-analysis.

BACKGROUND: Gambling behaviours have become of increased public health interest, but data on prevalence remain scarce. In this study, we aimed to estimate for adults and adolescents the prevalence of any gambling activity, the prevalence of engaging in specific gambling activities, the prevalence of any risk gambling and problematic gambling, and the prevalence of any risk and problematic gambling by gambling activity. METHODS: We performed a systematic review and meta-analysis. We systematically searched for peer-reviewed literature (on MEDLINE, Embase, and PsycInfo) and grey literature to identify papers published between Jan 1, 2010, and March 4, 2024. We searched for any gambling, including engagement with individual gambling activities, and problematic gambling data among adults and adolescents. We included papers that reported the prevalence or proportion of a gambling outcome of interest. We excluded papers of non-original data or based on a biased sample. Data were extracted into a bespoke Microsoft Access database, with the Joanna Briggs Institute Critical Appraisal Tool used to identify the risk of bias for each sample. Representative population survey estimates were firstly meta-analysed into country-level prevalence estimates, using metaprop, of any gambling, any risk gambling, problematic gambling, and by gambling activity. Secondly, population-weighted regional-level and global estimates were generated for any gambling, any risk gambling, problematic gambling, and specific gambling activity. This review is registered on PROSPERO (CRD42021251835). FINDINGS: We screened 3692 reports, with 380 representative unique samples, in 68 countries and territories. Overall, the included samples consisted of slightly more men or male individuals, with a mean age of 29·72 years, and most samples identified were from high-income countries. Of these samples, 366 were included in the meta-analysis. Globally, 46·2% (95% CI 41·7-50·8) of adults and 17·9% (14·8-21·2) of adolescents had gambled in the past 12 months. Rates of gambling were higher among men (49·1%; 45·5-52·6) than women (37·4%; 32·0-42·5). Among adults, 8·7% (6·6-11·3) were classified as engaging in any risk gambling, and 1·41% (1·06-1·84) were engaging in problematic gambling. Among adults, rates of problematic gambling were greatest among online casino or slots gambling (15·8%; 10·7-21·6). There were few data reported on any risk and problematic gambling among adolescent samples. INTERPRETATION: Existing evidence suggests that gambling is prevalent globally, that a substantial proportion of the population engage in problematic gambling, and that rates of problematic gambling are greatest among those gambling on online formats. Given the growth of the online gambling industry and the association between gambling and a range of public health harms, governments need to give greater attention to the strict regulation and monitoring of gambling globally. FUNDING: Australian National Health and Medical Research Council.

Transcriptomic landscape of mammalian ventral pallidum at single-cell resolution.

The ventral pallidum (VP) is critical for motivated behaviors. While contemporary work has begun to elucidate the functional diversity of VP neurons, the molecular heterogeneity underlying this functional diversity remains incompletely understood. We used snRNA-seq and in situ hybridization to define the transcriptional taxonomy of VP cell types in mice, macaques, and baboons. We found transcriptional conservation between all three species, within the broader neurochemical cell types. Unique dopaminoceptive and cholinergic subclusters were identified and conserved across both primate species but had no homolog in mice. This harmonized consensus VP cellular atlas will pave the way for understanding the structure and function of the VP and identified key neuropeptides, neurotransmitters, and neuro receptors that could be targeted within specific VP cell types for functional investigations. Teaser: Genetic identity of ventral pallidum cell types is conserved across rodents and primates at the transcriptional level.

Vaccine-Preventable Disease Outbreaks Among Healthcare Workers: A Scoping Review.

BACKGROUND: Outbreaks of vaccine-preventable diseases (VPDs) in healthcare workers (HCWs) can result in morbidity and mortality and cause significant disruptions to healthcare services, patients, and visitors as well as an added burden on the healthcare system. This scoping review aimed to describe the epidemiology of VPD outbreaks in HCWs caused by diseases that are prevented by the 10 vaccines recommended by the World Health Organization for HCWs. METHODS: In April 2022, CINAHL, MEDLINE, Global Health, and EMBASE were searched for all articles reporting on VPD outbreaks in HCWs since the year 2000. Articles were included regardless of language and study type. Clinical and epidemiological characteristics of VPD outbreaks were described. RESULTS: Our search found 9363 articles, of which 216 met the inclusion criteria. Studies describing 6 of the 10 VPDs were found: influenza, measles, varicella, tuberculosis, pertussis, and rubella. Most articles (93%) were from high- and upper-middle-income countries. While most outbreaks occurred in hospitals, several influenza outbreaks were reported in long-term-care facilities. Based on available data, vaccination rates among HCWs were rarely reported. CONCLUSIONS: We describe several VPD outbreaks in HCWs from 2000 to April 2022. The review emphasizes the need to understand the factors influencing outbreaks in HCWs and highlights the importance of vaccination among HCWs.

Prevalence of comorbid substance use disorders among people with opioid use disorder: A systematic review & meta-analysis.

BACKGROUND: Comorbid substance use disorders (SUDs) among people with opioid use disorder (OUD) contribute to poor clinical outcomes, including overdose and mortality. We present the first systematic review and meta-analysis to estimate the prevalence of specific non-opioid SUDs among people with OUD. METHODS: We searched Embase, PsycINFO, and MEDLINE from 1990 to 2022 for studies that used Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria to assess the prevalence of non-opioid SUDs among individuals with OUD. We used random-effects meta-analyses with 95% Confidence Intervals (CIs) to pool current and lifetime prevalence estimates separately. Meta-regressions and stratified meta-analyses were used to examine differences in prevalence estimates by sample characteristics and methodological factors. RESULTS: Of the 36,971 publications identified, we included data from 194 studies and 77,212 participants with OUD. The prevalence of any comorbid SUD among people with OUD was 59.5% (95%CI 49.1-69.5%) for current non-opioid SUDs, with 72.0% (95%CI 52.5-87.9%) experiencing a comorbid SUD in their lifetime. Of the studies that examined current comorbid SUDs, cocaine use disorder (30.5%, 95%CI 23.0-38.7%) was most common, followed by alcohol (27.1%, 95%CI 24.4- 30.0%), cannabis (22.7%, 95%CI 19.0-26.6%), sedative (16.1%, 95%CI 13.1-19.3%), and methamphetamine (11.4%, 95%CI 6.8-17.1%) use disorders. Substantial heterogeneity (I2>90%) across estimates was observed. Substantial heterogeneity (I2>90%) was observed across estimates, with significant variations in prevalence identified across geographic locations, recruitment settings, and other study-level factors. CONCLUSION: Findings from this study emphasize the importance of comorbid SUD treatment access for people with OUD. Our estimates can inform the provision of treatment and harm reduction strategies for people with OUD and specific subpopulations.

Collagen cross-link profiles and mineral are different between the mandible and femur with site specific response to perturbed collagen.

Compromises to collagen and mineral lead to a decrease in whole bone quantity and quality in a variety of systemic diseases, yet, clinically, disease manifestations differ between craniofacial and long bones. Collagen alterations can occur through post-translational modification via lysyl oxidase (LOX), which catalyzes enzymatic collagen cross-link formation, as well as through non-enzymatic advanced glycation end products (AGEs) such as pentosidine and carboxymethyl-lysine (CML). Characterization of the cross-links and AGEs, and comparison of the mineral and collagen modifications in craniofacial and long bones represent a critical gap in knowledge. However, alterations to either the mineral or collagen in bone may contribute to disease progression and, subsequently, the anatomical site dependence of a variety of diseases. Therefore, we hypothesized that collagen cross-links and AGEs differ between craniofacial and long bones and that altered collagen cross-linking reduces mineral quality in an anatomic location dependent. To study the effects of cross-link inhibition on mineralization between anatomical sites, beta-aminoproprionitrile (BAPN) was administered to rapidly growing, 5-8 week-old male mice. BAPN is a dose-dependent inhibitor of LOX that pharmacologically alters enzymatic cross-link formation. Long bones (femora) and craniofacial bones (mandibles) were compared for mineral quantity and quality, collagen cross-link and AGE profiles, and tissue level mechanics, as well as the response to altered cross-links via BAPN. A highly sensitive liquid chromatography/mass spectrometry (LC-MS) method was developed which allowed for quantification of site-dependent accumulation of the advanced glycation end-product, carboxymethyl-lysine (CML). CML was ∼8.3× higher in the mandible than the femur. The mandible had significantly higher collagen maturation, mineral crystallinity, and Young's modulus, but lower carbonation, than the femur. BAPN also had anatomic specific effects, leading to significant decreases in mature cross-links in the mandible, and an increase in mineral carbonation in the femur. This differential response of both the mineral and collagen composition to BAPN between the mandible and femur highlights the need to further understand how inherent compositional differences in collagen and mineral contribute to anatomic-site specific manifestations of disease in both craniofacial and long bones.

Campus Sexual Violence Prevention and Response: Lessons from a Pandemic to Inform Future Efforts.

The COVID-19 pandemic forced institutions of higher education to transition and work in ways that were new and innovative. Even though most colleges and universities transitioned to a virtual platform, the issues that students face continued, including sexual violence (SV). For many campus prevention and response professionals, reaching students during the pandemic posed unique challenges. The COVID-19 pandemic began when the project team was 18-months into a 4-year grant to administer and evaluate the efficacy of a SV prevention and response app, uSafeUS®, at 15 4-year colleges. In this paper, we describe the transition of engaging students with the app in traditional in-person settings to remote and hybrid learning settings. The project team, in collaboration with the campus partners, devised new ways to use the app to support victims of SV and their allies, along with campus professionals in their efforts to support students. These efforts included changes to collaboration (e.g., virtual platforms) and student engagement strategies. We describe how the lessons learned from this transition are important for continuing to engage campus communities in SV prevention and response, even as campuses slowly transitioned back to hybrid and in-person activities. The knowledge gained from this transition are attributable to an ongoing and open collaboration between campus practitioners and the project team.

Evaluation of micro-CT in the assessment of microleakage under bulk fill composite restorations.

PURPOSE: To evaluate microleakage measurements using micro-CT in comparison to dye tracers in Class 2 bulk-fill composite restorations with two adhesive techniques. METHODS: 60 sound molars were prepared with Class 2 cavities having cervical margins in enamel (mesial) and in dentin (distal) and restored with Filtek Bulk Fill, using either a self-etch or total-etch technique. All teeth were thermo-cycled between 5°C and 55°C for 800 cycles and randomly exposed to three tracer dyes: 2% methylene blue, 0.5% basic fuchsin or 50% silver nitrate solutions. Teeth were sectioned mesial-distal and depth of tracer penetration was measured as a ratio of dye penetration from the cavosurface divided by total depth of the cervical floor. The silver nitrate subgroup was micro-CT scanned prior to sectioning, evaluated in 3D serial sections, and calculated volumetrically. RESULTS: Analysis of ratios for dye tracer penetration showed significantly lower values for methylene blue (0.120). Micro-CT values calculated in 3D as volume (mm³) were significantly greater in enamel for self-etch (0.060) compared to total-etch (0.020). Micro-CT volumetric analysis showed better discrimination with significantly greater leakage in enamel margins using the self-etch adhesive. CLINICAL SIGNIFICANCE: Based on this in vitro study of microleakage, micro-CT volumetric evaluation in serial digital sections improves discrimination and represents a more reliable estimate of true microleakage. In vitro study of microleakage is most useful in comparing adhesive products, but clinical application of the data is questionable.

Loss of BMP signaling mediated by BMPR1A in osteoblasts leads to differential bone phenotypes in mice depending on anatomical location of the bones.

Bone morphogenetic protein (BMP) signaling in osteoblasts plays critical roles in skeletal development and bone homeostasis. Our previous studies showed loss of function of BMPR1A, one of the type 1 receptors for BMPs, in osteoblasts results in increased trabecular bone mass in long bones due to an imbalance between bone formation and bone resorption. Decreased bone resorption was associated with an increased mature-to-immature collagen cross-link ratio and mineral-matrix ratios in the trabecular compartments, and increased tissue-level biomechanical properties. Here, we investigated the bone mass, bone composition and biomechanical properties of ribs and spines in the same genetically altered mouse line to compare outcomes by loss of BMPR1A functions in bones from different anatomic sites and developmental origins. Bone mass was significantly increased in both cortical and trabecular compartments of ribs with minimal to modest changes in compositions. While tissue-levels of biomechanical properties were not changed between control and mutant animals, whole bone levels of biomechanical properties were significantly increased in association with increased bone mass in the mutant ribs. For spines, mutant bones showed increased bone mass in both cortical and trabecular compartments with an increase of mineral content. These results emphasize the differential role of BMP signaling in osteoblasts in bones depending on their anatomical locations, functional loading requirements and developmental origin.

Micro-computed Tomographic Evaluation of the Shaping Ability of WaveOne Gold, TRUShape, EdgeCoil, and XP-3D Shaper Endodontic Files in Single, Oval-shaped Canals: An In Vitro Study.

INTRODUCTION: This study evaluated and compared the shaping ability of the WaveOne Gold (Dentsply/Tulsa Dental Specialties, Tulsa, OK), TRUShape 3D Conforming File (Dentsply/Tulsa Dental Specialties), EdgeCoil (EdgeEndo, Albuquerque, NM), and XP-3D Shaper (Brasseler USA, Savannah, GA) endodontic file systems on oval-shaped canals using micro-computed tomographic (micro-CT) technology. METHODS: Thirty-two oval-shaped, single-canal extracted human teeth were decoronated 1 mm coronal to the cementoenamel junction and scanned via a micro-CT scanner (µCT100; Scanco Medical, Bassersdorf, Switzerland). Teeth were divided into 4 groups (n = 8) and instrumented according to the manufacturer's instructions. Coregistered images, before and after root canal preparation, were evaluated for morphometric measurements of the surface area, volume, structure model index (SMI), conicity, and percent of walls untouched using the manufacturer's evaluation software (IPL Register, Scanco Medical). Data were statistically compared between groups using 1-way analysis of variance and within groups using a paired sample t test. RESULTS: Instrumentation with all file types increased the surface area, volume, and conicity between and within groups. There was no statistically significant difference between the groups for any of the rotary instruments used (P < .05). CONCLUSIONS: Instrumentation of oval-shaped canals with WaveOne Gold, TRUShape, EdgeCoil, and XP-3D Shaper rotary endodontic instruments similarly increase the volume, surface area, and conicity. None of the file systems were capable of contacting all of the surface area in any canal.

Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments.

Bone morphogenetic protein (BMP) signaling pathways play critical roles in skeletal development and new bone formation. Our previous study, however, showed a negative impact of BMP signaling on bone mass because of the osteoblast-specific loss of a BMP receptor (i.e. BMPR1A) showing increased trabecular bone volume and mineral density in mice. Here, we investigated the bone quality and biomechanical properties of the higher bone mass associated with BMPR1A deficiency using the osteoblast-specific Bmpr1a conditional knockout (cKO) mouse model. Collagen biochemical analysis revealed greater levels of the mature cross-link pyridinoline in the cKO bones, in parallel with upregulation of collagen modifying enzymes. Raman spectroscopy distinguished increases in the mature to immature cross-link ratio and mineral to matrix ratio in the trabecular compartments of cKO femora, but not in the cortical compartments. The mineral crystallinity was unchanged in the cKO in either the trabecular or cortical compartments. Further, we tested the intrinsic material properties by nanoindentation and found significantly higher hardness and elastic modulus in the cKO trabecular compartments, but not in the cortical compartments. Four point bending tests of cortical compartments showed lower structural biomechanical properties (i.e. strength and stiffness) in the cKO bones due to the smaller cortical areas. However, there were no significant differences in biomechanical performance at the material level, which was consistent with the nanoindentation test results on the cortical compartment. These studies emphasize the pivotal role of BMPR1A in the determination of bone quality and mechanical integrity under physiological conditions, with different impact on femoral cortical and trabecular compartments.

Mechanical Loading Synergistically Increases Trabecular Bone Volume and Improves Mechanical Properties in the Mouse when BMP Signaling Is Specifically Ablated in Osteoblasts.

Bone homeostasis is affected by several factors, particularly mechanical loading and growth factor signaling pathways. There is overwhelming evidence to validate the importance of these signaling pathways, however, whether these signals work synergistically or independently to contribute to proper bone maintenance is poorly understood. Weight-bearing exercise increases mechanical load on the skeletal system and can improves bone quality. We previously reported that conditional knockout (cKO) of Bmpr1a, which encodes one of the type 1 receptors for Bone Morphogenetic Proteins (BMPs), in an osteoblast-specific manner increased trabecular bone mass by suppressing osteoclastogenesis. The cKO bones also showed increased cortical porosity, which is expected to impair bone mechanical properties. Here, we evaluated the impact of weight-bearing exercise on the cKO bone phenotype to understand interactions between mechanical loading and BMP signaling through BMPR1A. Male mice with disruption of Bmpr1a induced at 9 weeks of age, exercised 5 days per week on a motor-driven treadmill from 11 to 16 weeks of age. Trabecular bone volume in cKO tibia was further increased by exercise, whereas exercise did not affect the trabecular bone in the control genotype group. This finding was supported by decreased levels of osteoclasts in the cKO tibiae. The cortical porosity in the cKO bones showed a marginally significant decrease with exercise and approached normal levels. Exercise increased ductility and toughness in the cKO bones. Taken together, reduction in BMPR1A signaling may sensitize osteoblasts for mechanical loading to improve bone mechanical properties.

Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice.

There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months). We first assessed markers of bone turnover in control (non-loaded) mice. Serum osteocalcin and CTX declined significantly from 2 to 4 months (p<0.001). There were similar age-related declines in tibial mRNA expression of osteoblast- and osteoclast-related genes, most notably in late osteoblast/matrix genes. For example, Col1a1 expression declined 90% from 2 to 7 months (p<0.001). We then assessed tibial responses to mechanical loading using age-specific forces to produce similar peak strains (-1300 µÎµ endocortical; -2350 µÎµ periosteal). Axial tibial compression was applied to the right leg for 60 cycles/day on alternate days for 1 or 6 weeks. qPCR after 1 week revealed no effect of loading in young (2-month) mice, but significant increases in osteoblast/matrix genes in older mice. For example, in 12-month old mice Col1a1 was increased 6-fold in loaded tibias vs. controls (p = 0.001). In vivo microCT after 6 weeks revealed that loaded tibias in each age group had greater cortical bone volume (BV) than contralateral control tibias (p<0.05), due to relative periosteal expansion. The loading-induced increase in cortical BV was greatest in 4-month old mice (+13%; p<0.05 vs. other ages). In summary, non-loaded female BALB/c mice exhibit an age-related decline in measures related to bone formation. Yet when subjected to tibial compression, mice from 2-12 months have an increase in cortical bone volume. Older mice respond with an upregulation of osteoblast/matrix genes, which increase to levels comparable to young mice. We conclude that mechanical loading of the tibia is anabolic for cortical bone in young and middle-aged female BALB/c mice.

Matrix rigidity regulates a switch between TGF-ß1-induced apoptosis and epithelial-mesenchymal transition.

The transforming growth factor-ß (TGF-ß) signaling pathway is often misregulated during cancer progression. In early stages of tumorigenesis, TGF-ß acts as a tumor suppressor by inhibiting proliferation and inducing apoptosis. However, as the disease progresses, TGF-ß switches to promote tumorigenic cell functions, such as epithelial-mesenchymal transition (EMT) and increased cell motility. Dramatic changes in the cellular microenvironment are also correlated with tumor progression, including an increase in tissue stiffness. However, it is unknown whether these changes in tissue stiffness can regulate the effects of TGF-ß. To this end, we examined normal murine mammary gland cells and Madin-Darby canine kidney epithelial cells cultured on polyacrylamide gels with varying rigidity and treated with TGF-ß1. Varying matrix rigidity switched the functional response to TGF-ß1. Decreasing rigidity increased TGF-ß1-induced apoptosis, whereas increasing rigidity resulted in EMT. Matrix rigidity did not change Smad signaling, but instead regulated the PI3K/Akt signaling pathway. Direct genetic and pharmacologic manipulations further demonstrated a role for PI3K/Akt signaling in the apoptotic and EMT responses. These findings demonstrate that matrix rigidity regulates a previously undescribed switch in TGF-ß-induced cell functions and provide insight into how changes in tissue mechanics during disease might contribute to the cellular response to TGF-ß.

Low-magnitude whole-body vibration does not enhance the anabolic skeletal effects of intermittent PTH in adult mice.

Whole-body vibration (WBV) is a low-magnitude mechanical stimulus that may be anabolic for bone, yet we recently found that WBV did not improve bone properties in adult mice. Because intermittent parathyroid hormone (PTH) enhances the anabolic effects of high-magnitude skeletal loading, we sought to determine the skeletal effects of WBV in combination with PTH. Seven-month-old male BALB/c mice were assigned to six groups (n = 13-14/group) based on magnitude of applied acceleration (0 or 0.3 G) and PTH dose (0, 10, or 40 µg/kg/day). Mice were exposed to WBV (0.3 G, 90 Hz, sine wave) or sham loading (0 G) for 15 min/day, 5 days/week for 8 weeks. Vehicle or hPTH (1-34) was administered prior to each WBV session. Whole-body bone mineral content increased by ~ 5% from 0 to 8 weeks in the 40 µg/kg PTH group only, independent of WBV loading. Similarly, PTH treatment increased tibial cortical bone volume by ~5% from 0 to 8 weeks, independent of WBV loading. Neither PTH nor WBV stimulated trabecular bone formation. Consistent with the cortical bone effect, tibias from the 40 µg/kg PTH group had significantly greater ultimate force and energy to failure than tibias in the 0 and 10 µg/kg PTH groups, independent of WBV treatment. In summary, 8 weeks of intermittent PTH treatment increased cortical bone volume and strength in adult male BALB/c mice. Daily exposure to low-magnitude WBV by itself did not improve skeletal properties and did not enhance the PTH effect. No WBV-PTH synergy was found in this preclinical study.

Skeletal effects of whole-body vibration in adult and aged mice.

Low-amplitude, whole-body vibration (WBV) may be anabolic for bone. Animal studies of WBV have not evaluated skeletal effects in aged animals. We exposed 75 male BALB/c mice (7 month/young-adult; 22 month/aged) to 5 weeks of daily WBV (15 min/day, 5 day/wk; 90 Hz sine wave) at acceleration amplitudes of 0 (sham), 0.3, or 1.0 g. Whole-body bone mineral content (BMC) increased with time in 7 month (p < 0.001) but not 22 month (p = 0.34) mice, independent of WBV (p = 0.60). In 7 month mice, lower-leg BMC increased with time in 0.3 and 1.0 g groups (p < 0.005) but not in the sham group (p = 0.09), indicating a positive WBV effect. In 22 month mice, there were no changes with time in lower-leg BMC (p = 0.11). WBV did not affect tibial trabecular or cortical bone structure (by microCT), dynamic indices of trabecular or cortical bone formation, trabecular osteoclast surface, or the mass of the reproductive fat pad (p > 0.05). Each of these outcomes was diminished in 7 month versus 22 month animals (p < 0.05). In summary, 5 weeks of daily exposure to low-amplitude WBV had no skeletal effects in aged male mice. The potential of WBV to enhance bone mass in age-related osteoporosis is not supported in this preclinical study.

Type 1 diabetes in young rats leads to progressive trabecular bone loss, cessation of cortical bone growth, and diminished whole bone strength and fatigue life.

People with diabetes have increased risk of fracture disproportionate to BMD, suggesting reduced material strength (quality). We quantified the skeletal effects of type 1 diabetes in the rat. Fischer 344 and Sprague-Dawley rats (12 wk of age) were injected with either vehicle (Control) or streptozotocin (Diabetic). Forelimbs were scanned at 0, 4, 8, and 12 wk using pQCT. Rats were killed after 12 wk. We observed progressive osteopenia in diabetic rats. Trabecular osteopenia was caused by bone loss: volumetric BMD decreased progressively with time in diabetic rats but was constant in controls. Cortical osteopenia was caused by premature arrest of cortical expansion: cortical area did not increase after 4-8 wk in diabetic rats but continued to increase in controls. Postmortem muCT showed a 60% reduction in proximal tibial trabecular BV/TV in diabetic versus control rats, whereas moments of inertia of the ulnar and femoral diaphysis were reduced approximately 30%. Monotonic bending tests indicated that ulna and femora from diabetic animals were approximately 25% less stiff and strong versus controls. Estimates of material properties indicated no changes in elastic modulus or ultimate stress but modest ( approximately 10%) declines in yield stress for diabetic bone. These changes were associated with a approximately 50% increase in the nonenzymatic collagen cross-link pentosidine. Last, cyclic testing showed diminished fatigue life in diabetic bones at the structural (force) level but not at the material (stress) level. In summary, type 1 diabetes, left untreated, causes trabecular bone loss and a reduction in diaphyseal growth. Diabetic bone has greatly increased nonenzymatic collagen cross-links but only modestly reduced material properties. The loss of whole bone strength under both monotonic and fatigue loading is attributed mainly to reduced bone size.

Prediction of merozoite surface protein 1 and apical membrane antigen 1 vaccine efficacies against Plasmodium chabaudi malaria based on prechallenge antibody responses.

For the development of blood-stage malaria vaccines, there is a clear need to establish in vitro measures of the antibody-mediated and the cell-mediated immune responses that correlate with protection. In this study, we focused on establishing correlates of antibody-mediated immunity induced by immunization with apical membrane antigen 1 (AMA1) and merozoite surface protein 1(42) (MSP1(42)) subunit vaccines. To do so, we exploited the Plasmodium chabaudi rodent model, with which we can immunize animals with both protective and nonprotective vaccine formulations and allow the parasitemia in the challenged animals to peak. Vaccine formulations were varied with regard to the antigen dose, the antigen conformation, and the adjuvant used. Prechallenge antibody responses were evaluated by enzyme-linked immunosorbent assay and were tested for a correlation with protection against nonlethal P. chabaudi malaria, as measured by a reduction in the peak level of parasitemia. The analysis showed that neither the isotype profile nor the avidity of vaccine-induced antibodies correlated with protective efficacy. However, high titers of antibodies directed against conformation-independent epitopes were associated with poor vaccine performance and may limit the effectiveness of protective antibodies that recognize conformation-dependent epitopes. We were able to predict the efficacies of the P. chabaudi AMA1 (PcAMA1) and P. chabaudi MSP1(42) (PcMSP1(42)) vaccines only when the prechallenge antibody titers to both refolded and reduced/alkylated antigens were considered in combination. The relative importance of these two measures of vaccine-induced responses as predictors of protection differed somewhat for the PcAMA1 and the PcMSP1(42) vaccines, a finding confirmed in our final immunization and challenge study. A similar approach to the evaluation of vaccine-induced antibody responses may be useful during clinical trials of Plasmodium falciparum AMA1 and MSP1(42) vaccines.

Amygdala and hippocampal volumes in familial early onset major depressive disorder.

BACKGROUND: Abnormalities in the amygdala and hippocampus have been implicated in the pathogenesis of major depressive disorder (MDD). To our knowledge, no prior study has examined amygdala-hippocampus anatomy in pediatric patients with familial MDD (at least one first degree relative with MDD). METHODS: Thirty-two psychotropic-naive patients with familial MDD, aged 8-21 years (12 males and 20 females), and 35 group-matched healthy participants (13 males and 22 females) underwent volumetric magnetic resonance imaging in order to evaluate hippocampal and amygdala volumes. RESULTS: Patients with familial MDD had significantly smaller left hippocampal (p = .007, effect size [d] = .44) and right hippocampal volumes (p = .025, d = .33) than controls. No differences were noted in amygdala volumes between groups (right: p > .05, left: p > .05). No correlations between hippocampal or amygdala volumes and demographic or clinical variables were noted. CONCLUSIONS: Reduced hippocampal volume may be suggestive of a risk factor for developing MDD.