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1.
Trials ; 24(1): 707, 2023 Nov 04.
Article in English | MEDLINE | ID: mdl-37925441

ABSTRACT

BACKGROUND: Clinical trial evidence underpins evidence-based medicine and the improvement of healthcare worldwide. In Australasia, a significant proportion of clinical trials are conducted by geographically dispersed and multidisciplinary clinical researchers under the auspices of Clinical Trials Networks (CTNs). These groups play an important role in contributing to evidence-based medicine, primarily by conducting investigator-initiated clinical trials. Despite their clear benefits in terms of return on investment, CTNs suffer significant challenges. METHODS: We conducted surveys and focus groups with Australian and New Zealand CTNs to identifying the activities and attributes that enable CTNs to operate successfully. Based on our findings, we then conducted further surveys of Australian and New Zealand CTNs to identify the prevalence of these success factors in existing CTNs. RESULTS: Our focus groups identified three key themes associated with success and growth of a CTN: engaged membership, established infrastructure, and sustainability; and thirteen critical success factors: shared vision and motivation; strong leaders, governance and succession planning; an executive officer; sustainable funding for operations; effective communication; diverse representation and consumer input; transparent processes; a strong pipeline of trials; a reputable and recognised CTN brand; innovation and adaption; an effective group of network sites with a skilled workforce; embedded trials and prioritisation of research. These key themes and the relevant key areas were presented to 30 CTNs. Two factors were almost universally present in CTNs, reflecting the importance of these attributes: the presence of an executive officer, and a strong pipeline of trials. Three factors had a particularly low prevalence: sustainable funding for operations, effective communication, and embedded trials. CONCLUSIONS: By supporting both emerging and established CTNs to achieve critical success factors, we can improve the efficiency of CTNs to continue to contribute and expand their clinical trial activities. Particular focus needs to be on finding sustainable funding for CTNs, and raising awareness of the critical role undertaken by CTNs to improve healthcare and health outcomes.


Subject(s)
Delivery of Health Care , Humans , Australasia , Australia , New Zealand , Surveys and Questionnaires , Clinical Trials as Topic
2.
Biomed Mater ; 17(6)2022 09 15.
Article in English | MEDLINE | ID: mdl-36044886

ABSTRACT

Hyaluronic acid (HA) hydrogels have been used for a multitude of applications, perhaps most notably for tissue engineering and regenerative medicine, owing to the versatility of the polymer and its tunable nature. Various groups have investigated the impact of hydrogel parameters (e.g. molecular weight, concentration, stiffness, etc)in vitroandin vivoto achieve desired material performance characteristics. A limitation in the literature to date has been that altering one hydrogel parameter (a 'manipulated variable') to achieve a given hydrogel characteristic (a 'controlled variable') changes two variables at a time (e.g. altering molecular weight and/or concentration to investigate cell response to stiffness). Therefore, if cell responses differ, it may be possible that more than one variable caused the changes in observed responses. In the current study, we leveraged thiol-ene click chemistry with a crosslinker to develop a method that minimizes material performance changes and permitted multiple material properties to be independently held constant to evaluate a single variable at a time. Independent control was accomplished by tuning the concentration of crosslinker to achieve an effectively constant stiffness for different HA hydrogel molecular weights and polymer concentrations. Specific formulations were thereby identified that enabled the molecular weight (76-1550 kDa), concentration (2%-10%), or stiffness (∼1-350 kPa) to be varied while the other two were held constant, a key technical achievement. The response of rat mesenchymal stem cells to varying molecular weight, concentration, and stiffness demonstrated consistent upregulation of osteocalcin gene expression. The methodology presented to achieve independent control of hydrogel parameters may potentially be adopted by others for alternative hydrogel polymers, cell types, or cell culture medium compositions to minimize confounding variables in experimental hydrogel designs.


Subject(s)
Hyaluronic Acid , Hydrogels , Animals , Chondrogenesis , Hyaluronic Acid/chemistry , Hydrogels/chemistry , Molecular Weight , Polymers , Rats
3.
J Craniofac Surg ; 33(2): 607-609, 2022.
Article in English | MEDLINE | ID: mdl-34519712

ABSTRACT

ABSTRACT: The objective of this article is to assess the incidence of late bleeding following cleft palate repair (palatoplasty) in children. This is a retrospective review of a prospectively maintained database of patients treated for Cleft Lip and Palate in a tertiary academic pediatric hospital setting over 2 hospitals (Middlemore and Starship Hospitals) under the same multidisciplinary team of the Auckland Regional Cleft and Craniofacial Service, New Zealand. All patients with a diagnosis of Cleft Lip and/or Palate undergoing primary cleft palate repair over an 11 year period until March 2020 were included in the study. Our results found there were 482 patients with a new diagnosis of Cleft Lip and/or Palate from Jan 2009 through to March 2020. Three hundred sixty-six of those patients underwent primary palatoplasty at an average age of 10.5 months (range 8-18 months). The sub-types of cleft palate diagnoses were one-third Veau I, one-third Veau II, and the remaining one-third were Veau III, IV, and submucous cleft palate. One-third were syndromic. A total of 6 patients were re-admitted to hospital after discharge from their primary admission with bleeding from the cleft palate surgical site. Of the 6 patients re-admitted, 5 needed blood transfusions and 4 required an urgent return to the operating room. The authors found the rate of late bleeding following primary cleft palate repair in our unit is 1:61 operations or 1.6%. Late bleeding following cleft palate surgery is not well reported in the literature.


Subject(s)
Cleft Lip , Cleft Palate , Plastic Surgery Procedures , Child , Cleft Lip/surgery , Cleft Palate/surgery , Hemorrhage/surgery , Humans , Infant , Plastic Surgery Procedures/methods , Retrospective Studies
4.
Acta Biomater ; 104: 66-75, 2020 03 01.
Article in English | MEDLINE | ID: mdl-31904561

ABSTRACT

Bone regeneration of large cranial defects, potentially including traumatic brain injury (TBI) treatment, presents a major problem with non-crosslinking, clinically available products due to material migration outside the defect. Commercial products such as bone cements are permanent and thus not conducive to bone regeneration, and typical commercial bioactive materials for bone regeneration do not crosslink. Our previous work demonstrated that non-crosslinking materials may be prone to material migration following surgical placement, and the current study attempted to address these problems by introducing a new hydrogel system where tissue particles are themselves the crosslinker. Specifically, a pentenoate-modified hyaluronic acid (PHA) polymer was covalently linked to thiolated tissue particles of demineralized bone matrix (TDBM) or devitalized tendon (TDVT), thereby forming an interconnected hydrogel matrix for calvarial bone regeneration. All hydrogel precursor solutions exhibited sufficient yield stress for surgical placement and an adequate compressive modulus post-crosslinking. Critical-size calvarial defects were filled with a 4% PHA hydrogel containing 10 or 20% TDBM or TDVT, with the clinical product DBXⓇ being employed as the standard of care control for the in vivo study. At 12 weeks, micro-computed tomography analysis demonstrated similar bone regeneration among the experimental groups, TDBM and TDVT, and the standard of care control DBXⓇ. The group with 10% TDBM was therefore identified as an attractive material for potential calvarial defect repair, as it additionally exhibited a sufficient initial recovery after shearing (i.e., > 80% recovery). Future studies will focus on applying a hydrogel in a rat model for treatment of TBI. STATEMENT OF SIGNIFICANCE: Non-crosslinking materials may be prone to material migration from a calvarial bone defect following surgical placement, which is problematic for materials intended for bone regeneration. Unfortunately, typical crosslinking materials such as bone cements are permanent and thus not conducive to bone regeneration, and typical bioactive materials for bone regeneration such as tissue matrix are not crosslinked in commercial products. The current study addressed these problems by introducing a new biomaterial where tissue particles are themselves the crosslinker in a hydrogel system. The current study successfully demonstrated a new material based on pentenoate-modified hyaluronic acid with thiolated demineralized bone matrix that is capable of rapid crosslinking, with desirable paste-like rheology of the precursor material for surgical placement, and with bone regeneration comparable to a commercially available standard-of-care product. Such a material may hold promise for a single-surgery treatment of severe traumatic brain injury (TBI) following hemicraniectomy.


Subject(s)
Bone Regeneration/drug effects , Bone and Bones/physiology , Hyaluronic Acid/pharmacology , Hydrogels/pharmacology , Skull/physiology , Sulfhydryl Compounds/pharmacology , Tendons/physiology , Aged , Animals , Bone and Bones/drug effects , Cross-Linking Reagents/chemistry , Humans , Male , Middle Aged , Rats, Sprague-Dawley , Rheology , Tendons/drug effects
5.
Perfusion ; 35(3): 197-201, 2020 04.
Article in English | MEDLINE | ID: mdl-31480930

ABSTRACT

Extracorporeal membrane oxygenation is a safe modality of cardiorespiratory support for lung transplantation, with a reduction in coagulopathy and transfusion requirement when compared with cardiopulmonary bypass. In some scenarios, in lung transplantation, there are advantages to the use of cardiopulmonary bypass, which allows cardiac decompression, filtering of embolic air, easy addition and removal of volume, and a means to immediately reintroduce lost blood into circulation. We describe a novel circuit which allows safe and easy switch between modalities without prolonged interruption of flow. This circuit offers a safety net during surgery to minimise the risks influencing the use of extracorporeal membrane oxygenation.


Subject(s)
Extracorporeal Membrane Oxygenation/methods , Lung Transplantation/methods , Female , Humans , Middle Aged , Treatment Outcome
6.
Orthod Craniofac Res ; 22(3): 194-200, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30849215

ABSTRACT

OBJECTIVES: To (a) assess nasolabial outcomes across four main cleft subgroups, (b) assess agreement using a categorical and a continuous scoring measure and (c) compare outcomes to international studies. SETTINGS AND SAMPLE POPULATION: Analysis of 470 images of which 218 was unilateral cleft lip and palate (UCLP), 128 unilateral cleft lip (UCL), 90 bilateral cleft lip and palate (BCLP) and 34 bilateral cleft lip (BCL). Images were taken around five (n = 279) and eight-ten (n = 191) years of age. MATERIALS & METHODS: Cropped images were assessed using the Asher-McDade (AM) and a 100 mm visual analogue scale (VAS) by a panel of six raters. Scoring was undertaken for vermillion border and nasal form, symmetry and profile. Analysis was undertaken for each subscore, a total score with sensitivity analysis using a total score based on the subscores for each patient. AM intra- and inter-rater reliability was assessed using weighted kappa and for the VAS components reliability was assessed using Pearson correlation. RESULTS: The AM intra-rater reliability was moderate/substantial, whilst inter-rater reliability was fair. The VAS intra-rater correlations were high, and inter-rater correlations were moderate. Better outcomes were found with cleft lip (CL) vs cleft lip and palate (CLP). No differences were found for sex, ethnicity, age and cleft laterality (unilateral). The AM found no difference between unilateral or bilateral. The VAS found bilateral scored worse than unilateral for both CL and CLP. CONCLUSIONS: The nasolabial outcomes differ by cleft type. The correlation was relatively high for the VAS whilst the AM had relatively poor reliability.


Subject(s)
Cleft Lip , Cleft Palate , Esthetics, Dental , Humans , New Zealand , Reproducibility of Results
7.
Gene ; 639: 128-136, 2018 Jan 10.
Article in English | MEDLINE | ID: mdl-28987344

ABSTRACT

Non-Homologous End Joining (NHEJ) is a highly conserved pathway that repairs Double-Strand Breaks (DSBs) within DNA. Here we show that the deletion of yeast uncharacterized ORF HUR1, Hydroxyurea Resistance1 affects the efficiency of NHEJ. Our findings are supported by Protein-Protein Interaction (PPI), genetic interaction and drug sensitivity analyses. To assess the activity of HUR1 in DSB repair, we deleted its non-overlapping region with PMR1, referred to as HUR1-A. We observed that similar to deletion of TPK1 and NEJ1, and unlike YKU70 (important for NHEJ of DNA with overhang and not blunt end), deletion of HUR1-A reduced the efficiency of NHEJ in both overhang and blunt end plasmid repair assays. Similarly, a chromosomal repair assay showed a reduction for repair efficiency when HUR1-A was deleted. In agreement with a functional connection for Hur1p with Tpk1p and NEJ1p, double mutant strains Δhur1-A/Δtpk1, and Δhur1-A/Δnej1 showed the same reduction in the efficiency of plasmid repair, compared to both single deletion strains. Also, using a Homologous Recombination (HR) specific plasmid-based DSB repair assay we observed that deletion of HUR1-A influenced the efficiency of HR repair, suggesting that HUR1 might also play additional roles in other DNA repair pathways.


Subject(s)
DNA End-Joining Repair , Open Reading Frames , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae/genetics , Genes, Fungal
8.
N Z Med J ; 129(1440): 64-71, 2016 Aug 19.
Article in English | MEDLINE | ID: mdl-27538040

ABSTRACT

AIM: To determine the incidence of orofacial cleft at birth in New Zealand over 10 years from January 2000. METHODS: Comparison of data collected from cleft units and data held on the national minimum dataset. RESULTS: The overall incidence of OFC in New Zealand over a 10 year period was found to be 1.79 per 1,000 live births, higher than the norm for Western society. The major reason for this increased rate was an increased rate for the Maori 2.37 per 1,000 live births, specifically related to a Cleft Palate alone rate over twice that of the European (1.54 vs 0.73 per 1,000 live births). The rate for Pacific was half way between (1.04 per 1,000 live births). The rate of Cleft Lip alone was significantly lower in both Maori and Pacific populations. Different sex ratios were also seen in relation to Cleft Lip and Cleft Lip and Palate for Maori and Pacific compared to those normally reported. CONCLUSIONS: Maori have an increased incidence of Orofacial Cleft due to one of the highest rates of Cleft Palate alone in the world. Further aetiological studies involving genetic and environmental factors are required to elicit the reasons for this increased incidence.


Subject(s)
Cleft Lip/ethnology , Cleft Palate/ethnology , Live Birth , Female , Humans , Incidence , Infant, Newborn , Logistic Models , Male , Native Hawaiian or Other Pacific Islander , New Zealand/epidemiology , White People
9.
J Craniofac Surg ; 27(3): 598-601, 2016 May.
Article in English | MEDLINE | ID: mdl-27035602

ABSTRACT

The authors aimed to accurately assess the donor site morbidity from iliac crest bone grafts for secondary bone grafting in patients with cleft lip and palate alveolar defects. Fifty patients between 3 months and 10 years following alveolar bone grafting for cleft lip and palate were entered into the study. Two-thirds of patients had no significant concerns about the donor site. The remaining third had some concerns about the appearance of their hips and less than 10% of patients expressing strong agreement with statements about concerns with shape, appearance, and self-consciousness about the iliac crest donor site. Examination findings showed the average length of scar being 5.4 cm and a third of patients having some minor palpable boney irregularities of the iliac crest. The authors found that the alveolar crest donor site is well tolerated by patients long term but has a measurable morbidity long term.


Subject(s)
Alveolar Bone Grafting/methods , Cleft Lip/surgery , Cleft Palate/surgery , Ilium/transplantation , Tissue Donors , Adolescent , Child , Female , Follow-Up Studies , Humans , Male , Time Factors , Treatment Outcome
10.
PLoS One ; 9(1): e87248, 2014.
Article in English | MEDLINE | ID: mdl-24498054

ABSTRACT

One of the main mechanisms for double stranded DNA break (DSB) repair is through the non-homologous end-joining (NHEJ) pathway. Using plasmid and chromosomal repair assays, we showed that deletion mutant strains for interacting proteins Pph3p and Psy2p had reduced efficiencies in NHEJ. We further observed that this activity of Pph3p and Psy2p appeared linked to cell cycle Rad53p and Chk1p checkpoint proteins. Pph3/Psy2 is a phosphatase complex, which regulates recovery from the Rad53p DNA damage checkpoint. Overexpression of Chk1p checkpoint protein in a parallel pathway to Rad53p compensated for the deletion of PPH3 or PSY2 in a chromosomal repair assay. Double mutant strains Δpph3/Δchk1 and Δpsy2/Δchk1 showed additional reductions in the efficiency of plasmid repair, compared to both single deletions which is in agreement with the activity of Pph3p and Psy2p in a parallel pathway to Chk1p. Genetic interaction analyses also supported a role for Pph3p and Psy2p in DNA damage repair, the NHEJ pathway, as well as cell cycle progression. Collectively, we report that the activity of Pph3p and Psy2p further connects NHEJ repair to cell cycle progression.


Subject(s)
DNA End-Joining Repair , Nuclear Proteins/metabolism , Phosphoprotein Phosphatases/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/metabolism , Cell Cycle/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Checkpoint Kinase 1 , Checkpoint Kinase 2/genetics , Checkpoint Kinase 2/metabolism , DNA Breaks, Double-Stranded , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Mutation , Nuclear Proteins/genetics , Phosphoprotein Phosphatases/genetics , Protein Binding , Protein Interaction Mapping , Protein Kinases/genetics , Protein Kinases/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics
11.
J Immunol ; 190(1): 36-47, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23233728

ABSTRACT

T cell responses are characterized by the phenomenon of immunodominance (ID), whereby peptide-specific T cells are elicited in a reproducible hierarchy of dominant and subdominant responses. However, the mechanisms that give rise to ID are not well understood. We investigated the effect of viral dose on primary CD8(+) T cell (T(CD8+)) ID by injecting mice i.p. with various doses of influenza A virus and assessing the primary T(CD8+) response to five dominant and subdominant peptides. Increasing viral dose enhanced the overall strength of the T(CD8+) response, and it altered the ID hierarchy: specifically, NP(366-374) T(CD8+) were dominant at low viral doses but were supplanted by PA(224-233) T(CD8+) at high doses. To understand the basis for this reversal, we mathematically modeled these T(CD8+) responses and used Bayesian statistics to obtain estimates for Ag presentation, T(CD8+) precursor numbers, and avidity. Interestingly, at low viral doses, Ag presentation most critically shaped ID hierarchy, enabling T(CD8+) specific to the more abundantly presented NP(366-374) to dominate. By comparison, at high viral doses, T(CD8+) avidity and precursor numbers appeared to be the major influences on ID hierarchy, resulting in PA(224-233) T(CD8+) usurping NP(366-374) cells as the result of higher avidity and precursor numbers. These results demonstrate that the nature of primary T(CD8+) responses to influenza A virus is highly influenced by Ag dose, which, in turn, determines the relative importance of Ag presentation, T(CD8+) avidity, and precursor numbers in shaping the ID hierarchy. These findings provide valuable insights for future T(CD8+)-based vaccination strategies.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunodominant Epitopes/immunology , Influenza A virus/immunology , Influenza, Human/pathology , Lymphocytic choriomeningitis virus/immunology , Stem Cells/immunology , T-Lymphocyte Subsets/immunology , Viral Load/immunology , Animals , Antigen Presentation/immunology , CD8-Positive T-Lymphocytes/virology , Dose-Response Relationship, Immunologic , Female , Humans , Influenza, Human/immunology , Influenza, Human/metabolism , Lymphocyte Count , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred C57BL , Models, Immunological , Peptides/administration & dosage , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/virology
12.
Psychon Bull Rev ; 20(3): 566-73, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23242799

ABSTRACT

We evaluate two competing accounts of the relationship between beauty and category structure. According to the similarity-based view, beauty arises from category structure such that central items are favored due to their increased fluency. In contrast, the theory-based view holds that people's theories of beauty shape their perceptions of categories. In the present study, subjects learned to categorize abstract paintings into meaningfully labeled categories and rated the paintings' beauty, value, and typicality. Inconsistent with the similarity-based view, beauty ratings were highly correlated across conditions despite differences in fluency and assigned category structure. Consistent with the theory-based view, beautiful paintings were treated as central members for categories expected to contain beautiful paintings (e.g., art museum pieces), but not in others (e.g., student show pieces). These results suggest that the beauty of complex, real-world stimuli is not determined by fluency within category structure but, instead, interacts with people's prior knowledge to structure categories.


Subject(s)
Beauty , Esthetics/psychology , Judgment/physiology , Paintings/psychology , Visual Perception/physiology , Humans
13.
Vaccine ; 27(18): 2475-82, 2009 Apr 21.
Article in English | MEDLINE | ID: mdl-19368789

ABSTRACT

The effectiveness of single dose, intranasally delivered vaccines comprising detergent-disrupted inactivated influenza virus (split virus) and ISCOMATRIX adjuvant was examined in mice. Vaccines formulated with adjuvant required 10- to 100-fold less split virus antigen to induce pulmonary protection following viral challenge when compared to vaccines containing split virus alone. Furthermore, those formulated with ISCOMATRIX adjuvant elicited specific antibody in serum, saliva, vaginal, nasal and lung fluids when delivered to the entire respiratory tract. No specific antibody was detected in serum or mucosal samples, however, when the same vaccines were delivered using a procedure that restricted the inoculum to the nasal passages. Good protective responses can thus be achieved with only a single intranasal inoculation of influenza vaccine formulated with adjuvant, providing the vaccine can access sites of immune induction in the lower respiratory tract.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Antibodies, Viral/immunology , Cholesterol/administration & dosage , Influenza Vaccines/administration & dosage , Phospholipids/administration & dosage , Saponins/administration & dosage , Administration, Intranasal , Animals , Drug Combinations , Immunization , Influenza Vaccines/immunology , Mice , Mice, Inbred BALB C
14.
J Immunol ; 177(11): 7680-8, 2006 Dec 01.
Article in English | MEDLINE | ID: mdl-17114438

ABSTRACT

Primary CD8+ T cell (T(CD8+)) responses to viruses are directed toward multiple Ags and shaped by both the level of Ag presentation and the underlying Ag-specific T(CD8+) repertoire. The relative importance of these factors in deciding the hierarchy of T(CD8+) responses and how they are influenced by the immunoproteasome are not well understood. Using an influenza infection model in mice deficient in various immunoproteasome subunits, we observe that Ag presentation and T(CD8+) repertoire are altered in an epitope-specific and immunoproteasome subunit-dependent manner. More importantly, we find that the level of Ag presentation and the extent of the underlying repertoire can work either alone or in concert to determine definitively the magnitude of the individual T(CD8+) responses and hence the overall T(CD8+) hierarchy. Together, these results provide a clearer understanding of how immunodominance hierarchies are established.


Subject(s)
Antigen Presentation/immunology , CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Orthomyxoviridae Infections/immunology , Proteasome Endopeptidase Complex/immunology , Animals , Blotting, Western , Female , Mice , Mice, Knockout , Orthomyxoviridae/immunology , Proteasome Endopeptidase Complex/deficiency
15.
J Bone Miner Res ; 20(5): 809-16, 2005 May.
Article in English | MEDLINE | ID: mdl-15824854

ABSTRACT

UNLABELLED: Using a mechanical loading program to induce bone adaptation, we found that small (<2-fold) changes in the structural properties of the rat ulna increased its fatigue resistance >100-fold. This indicates that a moderate exercise program may be an effective preventative strategy for stress fractures. INTRODUCTION: There are currently limited preventative strategies for stress fractures. Because stress fracture risk is directly influenced by skeletal properties, it has been hypothesized that modification of these properties using a mechanical loading program may positively influence risk. The aim of this study was to investigate whether the bone changes associated with a mechanical loading program can enhance skeletal fatigue resistance. MATERIALS AND METHODS: Site-specific mechanical loading was performed on one forearm of adult female Sprague-Dawley rats using the axial compression loading model. Loading was performed 3 days/week for 5 consecutive weeks to induce adaptation. The loaded and nonloaded ulnas in each animal were removed after the loading program, and their material and structural properties were determined. The ulna pairs were subsequently loaded until fatigue failure at the same constant peak axial load. RESULTS: Mechanical loading induced consistent and predictable changes in the structural properties of loaded ulnas, with the largest change being a nearly 2-fold increase in midshaft minimum second moment of area (I(MIN)). The mechanical-loading induced bone changes resulted in a >100-fold increase in fatigue resistance in loaded ulnas, with resistance being exponentially related to the structural properties of the ulna. CONCLUSIONS: This study found that by enhancing the structural properties of a bone through a mechanical loading program, its fatigue resistance could be significantly improved. This indicates that an exercise program aimed at modifying bone structure may be used as a possible prevention strategy for stress fractures.


Subject(s)
Bone and Bones/pathology , Fractures, Stress/prevention & control , Physical Conditioning, Animal , Animals , Biomechanical Phenomena , Bone Density , Female , Fractures, Stress/metabolism , Models, Anatomic , Models, Biological , Muscle, Skeletal/pathology , Rats , Rats, Sprague-Dawley , Risk , Stress, Mechanical , Tensile Strength , Ulna/pathology
16.
Immunol Cell Biol ; 83(2): 119-28, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15748208

ABSTRACT

The immunostimulating complex or 'iscom' was first described 20 years ago as an antigen delivery system with powerful immunostimulating activity. Iscoms are cage-like structures, typically 40 nm in diameter, that are comprised of antigen, cholesterol, phospholipid and saponin. ISCOM-based vaccines have been shown to promote both antibody and cellular immune responses in a variety of experimental animal models. This review focuses on the evaluation of ISCOM-based vaccines in animals over the past 10 years, as well as examining the progress that has been achieved in the development of human vaccines based on ISCOM adjuvant technology.


Subject(s)
ISCOMs/immunology , Animals , Antigens/administration & dosage , CD8-Positive T-Lymphocytes/immunology , Cholesterol/immunology , Drug Combinations , Drug Delivery Systems , Humans , Immune System/immunology , Mice , Microscopy, Electron , Phospholipids/immunology , Saponins/immunology
17.
Endocrinology ; 146(2): 685-93, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15539550

ABSTRACT

Selective serotonin-reuptake inhibitors (SSRIs) antagonize the serotonin (5-hydroxytryptamine) transporter (5-HTT), and are frequently prescribed to children and adolescents to treat depression. However, recent findings of functional serotonergic pathways in bone cells and preliminary clinical evidence demonstrating detrimental effects of SSRIs on bone growth have raised questions regarding the effects of these drugs on the growing skeleton. The current work investigated the impact of 5-HTT inhibition on the skeleton in: 1) mice with a null mutation in the gene encoding for the 5-HTT; and 2) growing mice treated with a SSRI. In both models, 5-HTT inhibition had significant detrimental effects on bone mineral accrual. 5-HTT null mutant mice had a consistent skeletal phenotype of reduced mass, altered architecture, and inferior mechanical properties, whereas bone mineral accrual was impaired in growing mice treated with a SSRI. These phenotypes resulted from a reduction in bone formation without an increase in bone resorption and were not influenced by effects on skeletal mechanosensitivity or serum biochemistries. These findings indicate a role for the 5-HTT in the regulation of bone accrual in the growing skeleton and point to a need for further research into the prescription of SSRIs to children and adolescents.


Subject(s)
Bone Density/physiology , Bone Development/physiology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/genetics , Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Membrane Transport Proteins/genetics , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Animals , Bone Density/drug effects , Bone Development/drug effects , Fluoxetine/pharmacology , Mechanoreceptors/physiology , Membrane Glycoproteins/metabolism , Membrane Transport Proteins/metabolism , Mice , Mice, Inbred Strains , Mice, Mutant Strains , Nerve Tissue Proteins/metabolism , Phenotype , Serotonin Plasma Membrane Transport Proteins , Selective Serotonin Reuptake Inhibitors/pharmacology , Testosterone/blood
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