Reproductive outcomes following recurrent first-trimester miscarriage: a retrospective cohort study.

STUDY QUESTION: What are the subsequent reproductive outcomes (livebirths, miscarriages or other adverse pregnancy outcomes or no further pregnancy) of women with recurrent miscarriage (RM) attending a dedicated clinic? SUMMARY ANSWER: Of women with RM, 77% had a subsequent pregnancy, and among these pregnancies, the livebirth rate was 63%. WHAT IS KNOWN ALREADY: RM affects ∼1-3% of women of reproductive age. RM has known associations with advanced maternal age, obesity, diabetes, inherited thrombophilias, thyroid dysfunction, endometriosis and parental balanced translocations. However, ∼ 50% of women or couples will be left without an explanation for their pregnancy loss, even after completing investigations. RM is also associated with secondary infertility and adverse pregnancy outcomes including preterm birth and perinatal death. STUDY DESIGN SIZE DURATION: We undertook a retrospective cohort study to identify subsequent pregnancy outcomes in women with RM, defined as three consecutive first-trimester miscarriages. Women attending the RM clinic at a tertiary university hospital in the Republic of Ireland over 12 years (2008-2020) with a confirmed diagnosis of primary or secondary first-trimester RM were eligible for inclusion. In total, 923 charts were identified for review against the eligibility criteria. PARTICIPANTS/MATERIALS SETTING METHODS: Women with non-consecutive first-trimester miscarriages or ectopic pregnancy were excluded. Epidemiological and clinical information regarding medical history, investigation and management was gathered from paper and electronic medical records. Data were analysed using SPSS (Version 27). Associations between maternal characteristics and outcomes were explored using the χ2 test, with significance set at P < 0.05. Multinomial regression analysis was performed using a stepwise approach. MAIN RESULTS AND THE ROLE OF CHANCE: There were 748 women who were included; 332 (44%) had primary RM and 416 (56%) had secondary RM. The median age was 36 years (range 19-47). Foetal aneuploidy was the most common investigative finding (15%; n = 111/748); 60% had unexplained RM. In addition to supportive care, most women were prescribed aspirin (96%) and folic acid (75%). Of the 748 women, 573 had a subsequent pregnancy (77%) and 359 (48% of all women; 63% of pregnancies) had a livebirth, while 208 had a further pregnancy loss (28% of all women; 36% of pregnancies) and 6 were still pregnant at the end of the study. Women aged 35-39 years were more likely to have a livebirth than no further pregnancy (relative risk ratio (RRR): 2.29 (95% CI: 1.51-5.30)). Women aged 30-34 years were more likely to have a livebirth (RRR: 3.74 (95% CI: 1.80-7.79)) or a miscarriage (RRR: 2.32 (95% CI: 1.07-4.96)) than no further pregnancy. Smokers were less likely to have a livebirth (RRR: 0.37 (95% CI: 0.20-0.69)) or a miscarriage (RRR: 0.45 (95% CI: 0.22-0.90)) than no further pregnancy. Couples with an abnormal parental karyotype were less likely to have a miscarriage than no further pregnancy (RRR: 0.09 (95% CI: 0.01-0.79)). Including successive pregnancies conceived over the study period, the overall livebirth rate was 63% (n = 466/742), but this was reduced to 44% in women aged ≥40 years and 54% in women with infertility. LIMITATIONS REASONS FOR CAUTION: This work covers 13 years; however, those included in the later years have a shorter follow-up time. Although electronic health records have improved data availability, data collection in this cohort remains hampered by the absence of a formal booking visit for women presenting with miscarriage and a national miscarriage database or register. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are largely reassuring as most women with RM and hoping to conceive achieved a livebirth. In addition to older age, smoking and parental balanced translocations were associated with a reduced likelihood of further pregnancy. No investigation or treatment was associated with pregnancy outcome, reiterating the importance of the supportive aspects of care for women and their partners after RM and counselling regarding individual risk factors. This contributes to the limited international data on the investigative findings and treatment of women with RM. The high rate of prescribed medications merits greater scrutiny, in conjunction with other pregnancy outcomes, and reiterates the need for a national guideline on RM. STUDY FUNDING/COMPETING INTERESTS: L.A.L. is a PhD scholar funded through the Pregnancy Loss Research Group, Department of Obstetrics and Gynaecology, University College Cork. M.H. and C.F. are Postdoctoral Researchers on a project funded by the Health Research Board Ireland [ILP-HSR-2019-011] and led by K.O.D., titled: 'Study of the impact of dedicated recurrent miscarriage clinics in the Republic of Ireland'. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors have no conflicts of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

A novel placental tissue biologic, PTP-001, inhibits inflammatory and catabolic responses in vitro and prevents pain and cartilage degeneration in a rat model of osteoarthritis.

OBJECTIVE: Characterization of a novel human placental tissue-derived biologic, PTP-001, which is in development as a candidate therapeutic for the treatment of osteoarthritis symptoms and pathophysiology. METHODS: Human placental tissues from healthy donors were prepared as a particulate formulation, PTP-001. PTP-001 extracts were assayed for the presence of disease-relevant biofactors which could have beneficial effects in treating osteoarthritis. PTP-001 eluates were tested in human chondrocyte cultures to determine effects on the production of a key collagen-degrading matrix metalloproteinase, MMP-13. PTP-001 eluates were also assessed for anti-inflammatory potential in human monocyte/macrophage cultures, as well as for growth-stimulating anabolic effects in human synoviocytes. The in vivo effects of PTP-001 on joint pain and histopathology were evaluated in a rat model of osteoarthritis induced surgically by destabilization of the medial meniscus. RESULTS: PTP-001 was found to contain an array of beneficial growth factors, cytokines and anti-inflammatory molecules. PTP-001 eluates dose-dependently inhibited the production of chondrocyte MMP-13, and the secretion of proinflammatory cytokines from monocyte/macrophage cultures. PTP-001 eluates also promoted proliferation of cultured synovial cells. In a rat osteoarthritis model, PTP-001 significantly reduced pain responses throughout 6 weeks post-dosing. The magnitude and duration of pain reduction following a single intraarticular treatment with PTP-001 was comparable to that observed for animals treated with a corticosteroid (active control). For rats dosed twice with PTP-001, significant reductions in cartilage histopathology scores were observed. CONCLUSIONS: PTP-001 represents a promising biologic treatment for osteoarthritis, with a multi-modal mechanism of action that may contribute to symptom management and disease modification.

46, XX Male Disorder of Sexual Development.

Presentation A 47-year-old male was referred to endocrinology with a 9-year history of primary hypogonadism. Baseline testosterone was 4.3 nmol/L (RR 8-30) with an elevated follicle stimulating hormone (17.5 IU/L) and luteinizing hormone (15.2 mIU/ml). He had a short stature with bilateral small pre-pubertal testicles. Diagnosis Karyotyping showed 46 XX, making a diagnosis of 46, XX male disorder of sexual development. Fluorescence in situ hybridization analysis identified the presence of a translocated sex-determining region Y gene. Treatment Testosterone replacement therapy (testogel). Monitoring blood markers affected by testosterone therapy and metabolic risk factors. Conclusion Primary hypogonadism in males can be divided into congenital and acquired causes. 46, XX male disorder of sexual development is a rare congenital cause, with an incidence of approximately 1 in 20,000 newborn males. This case report highlights the value of karyotyping in the workup for primary hypogonadism.

Assessing the feasibility of using produced water for irrigation in Colorado.

The Colorado Water Plan estimates as much as 0.8 million irrigated acres may dry up statewide from agricultural to municipal and industrial transfers. To help mitigate this loss, new sources of water are being explored in Colorado. One such source may be produced water. Oil and gas production in 2016 alone produced over 300 million barrels of produced water. Currently, the most common method of disposal of produced water is deep well injection, which is costly and has been shown to cause induced seismicity. Treating this water to agricultural standards eliminates the need to dispose of this water and provides a new source of water. This research explores which counties in Colorado may be best suited to reusing produced water for agriculture based on a combined index of need, quality of produced water, and quantity of produced water. The volumetric impact of using produced water for agricultural needs is determined for the top six counties. Irrigation demand is obtained using evapotranspiration estimates from a range of methods, including remote sensing products and ground-based observations. The economic feasibility of treating produced water to irrigation standards is also determined using an integrated decision selection tool (iDST). We find that produced water can make a substantial volumetric impact on irrigation demand in some counties. Results from the iDST indicate that while costs of treating produced water are higher than the cost of injection into private disposal wells, the costs are much less than disposal into commercial wells. The results of this research may aid in the transition between viewing produced water as a waste product and using it as a tool to help secure water for the arid west.

Enablers and barriers to physical activity in overweight and obese pregnant women: an analysis informed by the theoretical domains framework and COM-B model.

BACKGROUND: Obesity during pregnancy is associated with increased risk of gestational diabetes mellitus (GDM) and other complications. Physical activity is a modifiable lifestyle factor that may help to prevent these complications but many women reduce their physical activity levels during pregnancy. Interventions targeting physical activity in pregnancy are on-going but few identify the underlying behaviour change mechanisms by which the intervention is expected to work. To enhance intervention effectiveness, recent tools in behavioural science such as the Theoretical Domains Framework (TDF) and COM-B model (capability, opportunity, motivation and behaviour) have been employed to understand behaviours for intervention development. Using these behaviour change methods, this study aimed to identify the enablers and barriers to physical activity in overweight and obese pregnant women. METHODS: Semi-structured interviews were conducted with a purposive sample of overweight and obese women at different stages of pregnancy attending a public antenatal clinic in a large academic maternity hospital in Cork, Ireland. Interviews were recorded and transcribed into NVivo V.10 software. Data analysis followed the framework approach, drawing on the TDF and the COM-B model. RESULTS: Twenty one themes were identified and these mapped directly on to the COM-B model of behaviour change and ten of the TDF domains. Having the social opportunity to engage in physical activity was identified as an enabler; pregnant women suggested being active was easier when supported by their partners. Knowledge was a commonly reported barrier with women lacking information on safe activities during pregnancy and describing the information received from their midwife as 'limited'. Having the physical capability and physical opportunity to carry out physical activity were also identified as barriers; experiencing pain, a lack of time, having other children, and working prevented women from being active. CONCLUSION: A wide range of barriers and enablers were identified which influenced women's capability, motivation and opportunity to engage in physical activity with "knowledge" as the most commonly reported barrier. This study is a theoretical starting point in making a 'behavioural diagnoses' and the results will be used to inform the development of an intervention to increase physical activity levels among overweight and obese pregnant women.

Investigating the Perceived Benefits, Barriers and Beliefs towards Physical Activity in Pregnancy among Women with Gestational Diabetes Mellitus.

Gestational Diabetes Mellitus (GDM) is a growing concern and poses serious health risks to both mother and child1. The current study explores the psychological determinants of exercise behaviour in a sample of pregnant women with GDM. A cross-sectional survey design was employed to examine exercise behaviour, illness perceptions, perceived barriers and benefits, exercise beliefs, and exercise self-efficacy using validated questionnaires. A sample of 46 pregnant women was recruited from University College Hospital Galway, Letterkenny General Hospital, Cork University Hospital and Mayo General Hospital in Castlebar. Participant's varied; age (22-44 years), body mass index (19-41). High mean scores for Personal Control (24.5) and Treatment Control (30.2) subscales indicated strongly held positive beliefs in relation to controllability of the illness. Total MET-min/week score was not related to any psychological variables. Analysis of the IPQ-R data revealed 'diet' (n=37, 80.4%) as the most referred to cause of diabetes. Exercise belief data identified "managing weight gain" (n= 21, 45.7%), and "losing baby weight" (n= 31, 67.4%) as the most frequent beliefs for engaging in physical activity during pregnancy and post pregnancy. Further research on the psychological determinants of physical activity behaviour among this population group is needed in order to create successful intervention strategies.

Risky sun tanning behaviours amongst Irish University students: a quantitative analysis.

BACKGROUND: Despite Ireland's temperate maritime climate, it has the third highest rate of malignant melanoma in the European Union, indicating the need to recognise tanning practices as a risky behaviour, especially amongst those most at risk (the younger population). AIM: To explore the factors associated with deliberate sun tanning amongst university students in Cork, Ireland. METHODS: Self-reported sun exposure, attitudes to tanning and sun protection practices were investigated using an online questionnaire in April 2010. RESULTS: There were 833 responses (8.33 %), mean age 22 years, 75 % female. Reporting deliberate tanning in the previous summer (n = 389, 46.7 %) was positively correlated (r = 0.622, p < 0.001) with stating an intention to tan next summer (n = 532, 63.9 %). Women and respondents with darker (vs. fairer) complexion were more likely to engage in deliberate tanning (p < 0.001). Deliberate tanning was associated with reporting enjoying tanning (p < 0.001), with reporting peer pressure into tanning (p = 0.039), and (marginally) with thinking it is worth getting burnt to get a tan (p = 0.068). Younger students were significantly more likely to report these attitudes; being a current smoker was associated with reporting peer pressure and that burning is worth a tan, indicating a level of risk-taking. Respondents reported (average) three sources of information on sun risks. CONCLUSION: Tanning is a form of strongly motivated risk-taking as much in a sun-limited country like Ireland as in hotter sun-rich climates. Risk communication strategies on sun exposure should be developed that target young people and improve their risk awareness.

Vibrational modes of GaN nanowires in the gigahertz range.

Brillouin-light-scattering measurements and finite-element modeling of vibrational spectra in the range of 5-40 GHz are presented for an array of monocrystalline GaN nanowires with hexagonal cross sections. Analysis of the spectra is substantially complicated by the presence of a distribution of nanowire diameters. The measurements and calculations reveal a variety of modes with simple flexural, higher-order flexural, approximately 'plane-strain', approximately longitudinal and torsional displacement patterns that are similar to the corresponding modes of isotropic cylinders. The largest peaks in the spectra with acoustic angular wavenumbers in the range of 4 to ~15 µm(-1) were determined to arise from modes with relatively large transverse displacements, consistent with inelastic light scattering arising predominantly from surface ripple. These dominant modes have finite frequencies in the limit of zero wavenumber, corresponding to transverse standing waves. At higher wavenumbers, the spectra provide evidence for increased scattering through elasto-optic coupling, especially with respect to the emergence of a peak from a mode analogous to the longitudinal guided modes of thin films.

Elevated aggrecanase activity in a rat model of joint injury is attenuated by an aggrecanase specific inhibitor.

OBJECTIVE: To evaluate aggrecanase activity after traumatic knee injury in a rat model by measuring the level of aggrecanase-generated Ala-Arg-Gly-aggrecan (ARG-aggrecan) fragments in synovial fluid, and compare with ARG-aggrecan release into joint fluid following human knee injury. To evaluate the effect of small molecule inhibitors on induced aggrecanase activity in the rat model. METHOD: An enzyme-linked immunosorbent assay (ELISA) was developed to measure ARG-aggrecan levels in animal and human joint fluids. A rat model of meniscal tear (MT)-induced joint instability was used to assess ARG-aggrecan release into joint fluid and the effects of aggrecanase inhibition. Synovial fluids were also obtained from patients with acute joint injury or osteoarthritis and assayed for ARG-aggrecan. RESULTS: Joint fluids from human patients after knee injury showed significantly enhanced levels of ARG-aggrecan compared to uninjured reference subjects. Similarly, synovial fluid ARG-aggrecan levels increased following surgically-induced joint instability in the rat MT model, which was significantly attenuated by orally dosing the animals with AGG-523, an aggrecanase specific inhibitor. CONCLUSIONS: Aggrecanase-generated aggrecan fragments were rapidly released into human and rat joint fluids after injury to the knee and remained elevated over a prolonged period. Our findings in human and preclinical models strengthen the connection between aggrecanase activity in joints and knee injury and disease. The ability of a small molecule aggrecanase inhibitor to reduce the release of aggrecanase-generated aggrecan fragments into rat joints suggests that pharmacologic inhibition of aggrecanase activity in humans may be an effective treatment for slowing cartilage degradation following joint injury.

Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance.

AIMS/HYPOTHESIS: Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. However, the physiological impact of TRIB3 action in vivo remains controversial. METHODS: We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic-hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO. RESULTS: Trib3 ASO treatment specifically reduced Trib3 expression by 70% to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic-hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70% and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment. CONCLUSIONS/INTERPRETATION: These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.

Elastic constants and dimensions of imprinted polymeric nanolines determined from Brillouin light scattering.

Elastic constants and cross-sectional dimensions of imprinted nanolines of poly(methyl methacrylate) (PMMA) on silicon substrates are determined nondestructively from finite-element inversion analysis of dispersion curves of hypersonic acoustic modes of these nanolines measured with Brillouin light scattering. The results for the cross-sectional dimensions, under the simplifying assumption of vertical sides and a semicircular top, are found to be consistent with dimensions determined from critical-dimension small-angle x-ray scattering measurements. The elastic constants C(11) and C(44) are found to be, respectively, 11.6% and 3.1% lower than their corresponding values for bulk PMMA. This result is consistent with the dimensional dependence of the quasi-static Young's modulus determined from buckling measurements on PMMA films with lower molecular weights. This study provides the first evidence of size-dependent effects on hypersonic elastic properties of polymers.

Co-culture of mechanically injured cartilage with joint capsule tissue alters chondrocyte expression patterns and increases ADAMTS5 production.

We studied changes in chondrocyte gene expression, aggrecan degradation, and aggrecanase production and activity in normal and mechanically injured cartilage co-cultured with joint capsule tissue. Chondrocyte expression of 21 genes was measured at 1, 2, 4, 6, 12, and 24h after treatment; clustering analysis enabled identification of co-expression profiles. Aggrecan fragments retained in cartilage and released to medium and loss of cartilage sGAG were quantified. Increased expression of MMP-13 and ADAMTS4 clustered with effects of co-culture, while increased expression of ADAMTS5, MMP-3, TGF-beta, c-fos, c-jun clustered with cartilage injury. ADAMTS5 protein within cartilage (immunohistochemistry) increased following injury and with co-culture. Cartilage sGAG decreased over 16-days, most severely following injury plus co-culture. Cartilage aggrecan was cleaved at aggrecanase sites in the interglobular and C-terminal domains, resulting in loss of the G3 domain, especially after injury plus co-culture. Together, these results support the hypothesis that interactions between injured cartilage and other joint tissues are important in matrix catabolism after joint injury.

Boundary mode frictional properties of engineered cartilaginous tissues.

Despite the fact that lubrication is a primary function of articular cartilage, there is little information on the frictional properties of cartilaginous engineered tissues. A biochemical mediator of cartilage frictional properties in boundary lubrication, lubricin, has been shown to be secreted from chondrocyte-hydrogel constructs. In the current studies we utilized articular chondrocytes (CON), meniscal fibrochondrocytes (MEN), and mesenchymal stem cells (MSC) in alginate cultures to determine lubricin localization and the inherent boundary lubrication friction coefficient. Additionally, we investigated the ability of these tissues to be lubricated by synovial fluid and the reversibility of this lubrication. Cell-alginate constructs were cultured over six weeks, culture medium assayed for lubricin release by ELISA and constructs analyzed with immunohistochemical (IHC) methods to investigate the localization of lubricin. Engineered tissues were tested in a custom friction instrument to determine the equilibrium friction coefficient (microeq) in boundary lubrication mode, following incubation with equine synovial fluid (SF), and subsequent extraction in l.5M NaCl. MSCs released 10 fold more lubricin than CON or MEN cultures. IHC analysis showed no localization of lubricin to alginate, minimal focal staining of engineered constructs at six weeks in culture, and the ability of all engineered tissues to localize lubricin when exogenously treated with SF. Frictional characterization showed no difference in microeq over culture for all engineered tissues, while incubation in SF decreased microeq for all tissues over culture duration, and extraction of lubricin resulted in a loss of lubrication of all engineered tissues.

Bioregulation of lubricin expression by growth factors and cytokines.

Lubricin, also commonly referred to as superficial zone protein (SZP) and proteoglycan 4 (PRG4), is a multifaceted, cytoprotective glycoprotein that contributes to the boundary lubrication properties facilitating low friction levels at interfacing surfaces of articular cartilage. Biological processes effecting the gain or loss of lubricin function may therefore have important consequences relevant to joint physiology and pathology. Herein, we describe experiments conducted to extend our understanding of the influence of various cytokines and growth factors on lubricin gene expression and protein secretion in synovial tissues. Exposure of synoviocytes, chondrocytes and cartilage explants to proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) results in a marked reduction in the expression and/or abundance of secreted lubricin, with corresponding alterations in the amounts of cartilage-associated (boundary) lubricin. Conversely, treatment with transforming growth factor-beta (TGF-beta) significantly upregulates lubricin synthesis, secretion and cartilage boundary association. Oncostatin M also appears to be capable of modulating lubricin metabolism, with the potential to induce lubricin synthesis by chondrocytes. Collectively, the results of studies on cytokine and growth factor regulation of lubricin biosynthesis and biodistribution may help provide new insights and therapeutic perspectives for promoting joint function.

Cytokine induced metalloproteinase expression and activity does not correlate with focal susceptibility of articular cartilage to degeneration.

OBJECTIVE: To determine whether the focal susceptibility to cartilage degeneration in joints is related to a differential response to cytokine stimulation. METHODS: Compare aggrecan and collagen catabolism in in-vitro models of cartilage degradation induced by retinoic acid (RA), interleukin-1 (IL-1), tumor necrosis factor alpha (TNF) and IL-1 plus oncostatin M (OSM). Glycosaminoglycan (GAG) and hydroxyproline (HyPro) quantification and Western immunoblot analyses of aggrecan and collagen degradation products were undertaken in explant cultures of normal cartilage from regions of equine joints with a known high and low susceptibility to degeneration in disease. RNA isolation and semi quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis were performed to determine the expression of aggrecanases, matrix metalloproteinases (MMPs) and their inhibitors. RESULTS: Although the rate of basal cartilage aggrecan turnover was dependent on joint region there was no difference in the response of different cartilages to cytokines. Individual animals did show a significant difference in the response of certain cartilages to cytokines, with both decreased and increased aggrecan loss in cartilage with a low susceptibility to degeneration. Aggrecan release in both short- and long-term cultures from all cartilages was associated with increased cleavage by aggrecanases rather than MMPs. There was a poor correlation between expression of aggrecanases, MMPs or their inhibitors and cytokine induced aggrecan catabolism. IL-1 alone was able to stimulate collagen breakdown in equine articular cartilage and surprisingly, significantly more collagen loss was induced in cartilage from regions less susceptible to degeneration. CONCLUSIONS: Collectively, these studies suggest that a regional difference in response to catabolic cytokines is unlikely to be a factor in the initiation of focal cartilage degeneration in osteoarthritis (OA).

A mechanism underlying the movement requirement for synovial joint cavitation.

Many studies have highlighted the importance of movement-induced mechanical stimuli in the development of functional synovial joints. However, such phenomenological results have failed to provide a full explanation of the mechanism essential for the morphogenesis of fluid-filled joint cavities. We have previously demonstrated that the large glycosaminoglycan hyaluronan (HA), in association with its principal cell surface receptor CD44, plays a major role during the morphogenesis of chick joints. We have taken cells from the surface of recently cavitated joints and subjected them to a brief period of dynamic mechanical strain (3800 microE for 10 min) and measured changes in HA synthesis/release, CD44 expression and HA synthase gene expression. In addition, we subjected cells to matrix depletion prior to the application of mechanical strain in order to examine any potential modulatory function of the ECM during the cell response to strain. Removal of the cell-associated HA-containing matrix with hyaluronidase significantly increased the release of HA into tissue culture media over 24 h and is associated with increased CD44 expression, alterations in HA synthase gene expression and enhanced binding of HA to the cell surface. Such changes in HA release were shown to be blocked by addition of exogenous HA and synergistically enhanced by the application of dynamic mechanical strain. These results show that cell-matrix interactions modify the response of embryonic cells to mechanical strain and provide further insight into the mechano-dependent mechanism of joint cavity morphogenesis.

Study of porosity and stiffness measurement of nanoporous aerogel films with wideband ultrasonic surface waves.

Nanoporous aerogel films are of great scientific and commercial interest because of their outstanding potential for application to microelectronic interconnect, associated with low dielectric constant. Of the parameters which describe such aerogel films, density/porosity and stiffness are two of the most critical, but are difficult to measure. This paper shows how measurement of the dispersion of laser-generated surface acoustic wavepackets travelling on submicron-thick aerogel films on silicon substrates allows the density and Young's modulus to be extracted reliably. Particular attention is paid to accuracy of measurements and sensitivity to input data; and a method for extracting measurements on very thin films (<300 nm) is presented.

Effects of surface roughness on surface acoustic wave propagation in semiconductor materials.

The effect of surface roughness on adhesion and tribological properties of films and interfaces is of key importance. Therefore, it is of utmost importance to be able to measure this quantity and to predict the effects that different roughness levels may cause. Roughness affects the propagation of surface acoustic waves on a material but there is little useful quantitative data on the topic. This work investigates the dispersive effect of roughness on surface acoustic wavepackets (30-200 MHz frequency range) for different degrees of nanometer roughness on silicon (0 0 1) and (1 1 1) surfaces, we show that the roughness-induced frequency dispersion effect is significant, and that although available theories agree qualitatively with the results, the theory is not adequate to predict the real SAW dispersion. These experimental results have considerable implications for design of SAW devices, for accuracy of Brillouin spectroscopy measurements, and for possible applications to non-destructive testing of materials. Previously unknown dispersive effects on anisotropic crystal surfaces are also demonstrated.

IL-6 and its soluble receptor augment aggrecanase-mediated proteoglycan catabolism in articular cartilage.

Elevated concentrations of interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6R) in the synovial fluids and serum of patients with arthritis have been implicated in the joint tissue destruction associated with these conditions, however studies conducted to date on the role and effects of IL-6 in the process of cartilage proteoglycan (aggrecan) catabolism are disparate. In the present study, bovine articular cartilage explants were maintained in a model organ culture system in the presence or absence of IL-1alpha or TNF-alpha, and under co-stimulation with or without IL-6 and/or sIL-6R. After measuring proteoglycan loss from the explants, the proteolytic activity and expression profiles of aggrecanase(s) was assessed for each culture condition. Stimulation of cartilage explants with IL-6 and/or sIL-6R potentiated aggrecan catabolism and release above that seen in the presence of IL-1alpha or TNF-alpha alone. This catabolism was associated with aggrecanase (but not MMP) activity, with correlative mRNA expression for aggrecanase-2.