The effect of surface chemistry modification of titanium alloy on signalling pathways in human osteoblasts

Establishing and maintaining mature bone at the bone–device interface is critical to the long-term success of prosthesis. Poor cell adhesion to orthopaedic and dental implants results in implant failure. Considerable effort has been devoted to alter the surface characteristics of these biomaterials in order to improve the initial interlocking of the device and skeleton. We investigated the effect of surface chemistry modification of titanium alloy (Ti–6Al–4V) with zinc, magnesium or alkoxide-derived hydroxy carbonate apatite (CHAP) on the regulation of key intracellular signalling proteins in human bone-derived cells (HBDC) cultured on these modified Ti–6Al–4V surfaces. Western blotting demonstrated that modifying Ti–6Al–4V with CHAP or Mg results in modulation of key intracellular signalling proteins. We showed an enhanced activation of Shc, a common point of integration between integrins and the Ras/Mapkinase pathway. Mapkinase pathway was also upregulated, suggesting its role in mediating osteoblastic cell interactions with biomaterials. The signalling pathway involving c-fos (member of the activated protein-1) was also shown to be upregulated in osteoblasts cultured on the Mg and CHAP modified Ti–6Al–4V. Thus surface modification with CHAP or Mg may contribute to successful osteoblast function and differentiation at the skeletal tissue–device interface.     

The reliability and validity of the Seasonal Pattern Assessment Questionnaire: a comparison between patient groups

Background: The Seasonal Pattern Assessment Questionnaire (SPAQ) is a frequently used screening instrument in the research on Seasonal Affective Disorder (SAD). Nevertheless, studies on its reliability and validity are relatively scarce. In the present study the reliability and the contrast validity of the SPAQ are investigated. Methods: SAD patients, selected by means of a clinical interview, non-seasonal depressed out-patients, non-depressed out-patients, and a control group, are contrasted to estimate the discriminating power of the SPAQ. Also, the reliability and factor structure of the seasonality and the climate subscales are investigated. To study food intake the Seasonal Food Preference Questionnaire (SFPQ) was developed. Results: The SAD criterion of the SPAQ shows good specificity (94%), but a low sensitivity (44%). Discriminant analysis shows sufficient ability to classify subjects (81% correctly classified). The Global Seasonality Scale has a good internal consistency. It consists of two factors, a psychological factor and a food factor. The SFPQ is sensitive for carbohydrate intake by SAD patients. Limitations: Most SAD patients had received treatment and completed the SPAQ while they were not depressed, which may have influenced the sensitivity. Conclusions: The SPAQ is not sensitive enough to be considered a diagnostic instrument for SAD. Nevertheless, it is accurate enough to be used as a screenings instrument. The only false positives were found in the depressive group. The accuracy of prevalence Figs. can be improved by completion of the SPAQ in the summer months, combined with the completion of a depression scale.     

Antigen location contributes to the pathological features of a transplanted heart graft

Organ-specific injury after transplantation presents with a variety of clinical and pathological phenotypes, yet the factors influencing development of each outcome are poorly understood. Because primed T lymphocytes must re-encounter their antigen within the target organ to engage effector functions, we postulated that the cellular location of antigen within that organ could significantly impact the induced pathology. We challenged female Marilyn CD4 T-cell receptor transgenic mice, in which all T cells are specific for the male minor transplantation antigen, with male heart transplants expressing the relevant peptide: major histocompatibility complex on either graft parenchymal/vascular cells or alternatively, on graft-infiltrating mononuclear cells. The two different graft donors led to equivalent activation of recipient T cells as assessed by frequency, cell surface marker expression, cytokine production, and the ability to traffic to the graft. Nonetheless, if the target antigen was expressed on graft vascular and/or parenchymal cells, the outcome was acute graft destruction. In contrast, if the antigen was expressed only on graft-infiltrating mononuclear cells the same effector T-cell repertoire caused chronic rejection and vasculopathy. This unique result, that target antigen location can influence pathological outcome, has significant implications for understanding the pathogenesis of chronic allograft injury in humans.     

Non-linear cardiac output dynamics during ramp-incremental cycle ergometry

Published literature asserts that cardiac output (=O₂×1/C_(a-v)O₂) increases as a linear function of oxygen uptake with a slope of approximately 5–6 during constant work rate exercise. However, we have previously demonstrated that C_(a-v)O₂ has a linear relationship as a function of O₂ during progressively increasing work rate incremental exercise. Therefore, we hypothesized that may indeed have a non-linear relationship with respect to O₂ during incremental, non-steady state exercise. To investigate this hypothesis, we performed five maximal progressive work rate exercise studies in healthy human subjects. was determined every minute during exercise using measured breath-by-breath O₂, and arterial and pulmonary artery measurements of PO₂, hemoglobin saturation, and content. was plotted as a function of O₂ and the linear and non-linear (first order exponential and hyperbolic) fits determined for each subject. Tests for linearity were performed by assessing the significance of the quadratic terms added to the linear relation using least squares estimation in linear regression. Linearity was inadequate in all cases (group P<0.0001). We conclude that cardiac output is a non-linear function of O₂ during ramp-incremental exercise; the pattern of non-linearity suggests that while the kinetics of are faster than those of O₂ they progressively slow as work rate (and O₂) increases.     

The origins of life -- the 'protein interaction world' hypothesis: protein interactions were the first form of self-reproducing life and nucleic acids evolved later as memory molecules

The 'protein interaction world' (PIW) hypothesis of the origins of life assumes that life emerged as a self-reproducing and expanding system of protein interactions. In mainstream molecular biology, 'replication' refers to the material copying of molecules such as nucleic acids. However, PIW is conceptualized as an abstract communication system constituted by the interactions between proteins, in which 'replication' happens at the level of self-reproduction of these interactions between proteins. Densely concentrated peptide interaction systems may have reproduced and expanded as 'protocell' vesicles surrounded by lipid bi-layer membranes. Protocells led to the emergence of proto-RNA molecules of greater chemical stability which served as chemically differentiated 'memories' of peptide interaction states, thereby facilitating the reproduction and expansion of protocells. Simplification-driven expansion led to the selection of biotic amino acids and the reduction of the typical RNA alphabet to the four usual bases (A, C, G and U). Dense interactions between RNA molecules led to the emergence of the RNA interaction subsystem of the cell, and to the emergence of 'memories' of RNA interactions in the form of DNA molecules with greater chemical stability. The expansion of DNA molecule interactions led to the dense clustering and encapsulation of DNA molecules within the cell nucleus. RNA molecules therefore serve as memories of protein interactions and DNA molecules are memories of RNA interactions. We believe that the PIW hypothesis is more evolutionarily plausible than the mainstream RNA world hypothesis, and has greater explanatory power.     

The Genetic Relationship Between Social Cognition and Conduct Problems

Studies of children and adolescents with conduct problems suggest both genetic and environmental influences on population variance. Any genetic influence is likely to be complex and to act via mediating attributes of personality or cognitive style. One potential mediating attribute is social cognitive ability, as conduct problems have been shown to be associated with deficient social cognitive skills. The current investigation has examined the correlation between conduct problems and social cognition and has investigated the genetic and environmental influences on these measures and their covariation using a twin design. A population-based sample of twins aged 5-17 was used to examine the genetic relationship between conduct problems and social cognition using parent-report questionnaires. Conduct problems and social cognition were found to be highly correlated and to share common genetic influences that accounted for about half the covariation in scores. Each phenotype was subject to its own environmental influences that were not shared.     

Mode of delivery and risk of allergic rhinitis and asthma

BACKGROUND: It has been hypothesized that cesarean section might increase the risk of developing allergic disease by depriving the fetus and newborn of exposure to maternal microflora. Furthermore, it has been suggested that complicated modes of delivery might be associated with an increased risk of asthma. OBJECTIVE: The purpose of this investigation was to study whether cesarean section and other complicated modes of delivery are associated with an increased risk of allergic rhinitis or asthma. METHODS: Information on self-reported allergic rhinitis, asthma ever, current asthma, and occupation was obtained from 9722 singleton women born in Denmark during the period 1973-1977 who participated in a national cohort study during the period 1997-2001. For these women, information was available on mode of delivery (spontaneous delivery, cesarean section, vacuum extraction, or other complicated mode of delivery, such as rotation/traction or use of forceps), gestational age, birth weight, and length at birth from the Danish Medical Birth Register. Information on parity and maternal age was obtained from the Danish Civil Registration System. RESULTS: The odds ratios (ORs) of allergic rhinitis were 1.16 (95% CI, 0.90-1.49) for cesarean section and 1.06 (95% CI, 0.85-1.32) for other complicated modes of delivery in comparison with spontaneous delivery. The corresponding ORs of asthma ever were 1.33 (95% CI, 1.02-1.74) and 1.18 (95% CI, 0.94-1.49) for cesarean section and other complicated modes of delivery, respectively, and the ORs of current asthma were 1.22 (95% CI, 0.87-1.73) and 1.26 (95% CI, 0.94-1.68), respectively, in comparison with spontaneous delivery. CONCLUSIONS: Our findings do not support the hypothesis that cesarean section or other complicated modes of delivery are associated with the development of allergic rhinitis. However, there might be a positive association with development of asthma--in particular, for cesarean section--that was not explained by gestational age, birth weight, ponderal index, smallness for gestational age, parity, maternal age, or occupation.     

Predicting pregnancy and spermatogenesis by survival analysis during gonadotrophin treatment of gonadotrophin-deficient infertile men

BACKGROUND: Predictors of fertility or spermatogenesis during gonadotrophin therapy of gonadotrophin-deficient men remain poorly defined. METHODS AND RESULTS: In order to evaluate potential predictors, this study evaluated 29 consecutive gonadotrophin-deficient men all desiring paternity who received 43 courses of therapy in one centre between 1982 and 1998. The Kaplan-Meier survival analysis estimates of median (SE) time to a sperm concentration of >0, >5 and >20 x 10(6)/ml were 5.5 (1.1), 12.4 (2.3) and 29.1 (1.9) months respectively. Conception occurred in 22/43 cycles (with eight men achieving two pregnancies) with a median (SE) Kaplan-Meier estimate of 20.5 (4.7) months. The median sperm concentration at conception was 5.0 (SE 2.0; range 0.0-59.5) x 10(6)/ml. Multivariate correlated Cox proportional hazards models predicting these same sperm thresholds and conception were developed by forward stepwise variable selection with verification of the model by backward stepping. Larger testicular volume, prior gonadotrophin therapy, completion of puberty, older age, the absence of adverse fertility factors and the absence of multiple pituitary hormone deficiency predicted a favourable response. Multivariate modelling suggests that the two most important predictors of sperm output are testicular volume and pubertal status. The most important potentially modifiable predictor was prior gonadotrophin therapy. The efficacy of recombinant and urinary FSH were similar. Prior androgen therapy and partner's age did not appear to be significant. CONCLUSIONS: Since prolonged treatment may be required to induce spermatogenesis, attention to these predictors may allow appropriate early use of advanced reproductive technologies.     

Recombinant allergens promote expression of CD203c on basophils in sensitized individuals

BACKGROUND: Traditionally, the diagnosis of type I allergies is based on clinical data, skin test results, and laboratory test results with allergen extracts. During the past few years, several attempts have been made to refine diagnostic assays in clinical allergy by introducing recombinant allergens and novel markers of IgE-dependent cell activation. OBJECTIVES: We have identified the ectoenzyme CD203c as a novel basophil antigen that is upregulated on IgE receptor cross-linkage. In this study we applied CD203c and a panel of recombinant allergens to establish a novel basophil test that allows for a reliable quantification of IgE-dependent responses at the effector cell level. METHODS: Patients allergic to birch (Bet v 1, n = 15; Bet v 2, n = 8) and grass (Phl p 1, n = 15; Phl p 2, n = 10; Phl p 5, n = 14) pollen allergens, as well as 10 nonallergic donors, were examined. Basophils were exposed to various concentrations of recombinant allergens for 15 minutes and then examined for expression of CD203c by means of flow cytometry. CD203c upregulation was correlated with the increase in CD63. RESULTS: Exposure to recombinant allergens resulted in a dose-dependent increase in expression of CD203c on peripheral blood basophils in sensitized individuals, whereas no increase was seen in healthy control subjects. The effects of the recombinant allergens on CD203c expression were also time dependent. There was a good correlation between allergen-induced upregulation of CD203c and upregulation of CD63 (R = 0.76). CONCLUSION: Flow cytometric quantitation of CD203c on blood basophils exposed to recombinant allergens is a useful approach to determine the allergic state in sensitized individuals and represents a basis for a sensitive novel allergy test.