Water and T-maze protocols are equally efficient methods to assess spatial memory in 3xTg Alzheimer's disease mice.

Rodent spatial memory is commonly tested using the water-maze; however, there is a potential confound of stress on learning in this behavioural paradigm. This is particularly relevant when testing spatial memory in models of neurodegeneration, such as the 3xTg mouse model for Alzheimer's disease. Here, we first confirmed that 3xTgAD mice express fear conditioning and then compared the performance of young and middle-aged mice on short-duration versions of the radial arm water-maze (RAWM) and the minimally stressful T-maze spontaneous alternation task. Our main questions were: (1) does the reliance on stressors in water-maze training mask the true cognitive ability of 3xTgAD mice; and (2) are 3xTgAD mice similarly impaired in water-maze and T-maze protocols. Firstly, male and female 3xTgAD mice displayed intact freezing responses in both contextual and Pavlovian fear conditions. As male 3xTgAD mice displayed relatively enhanced fear responses the remaining tests were performed using only female 3xTgAD and control mice in order to equate for response to stressors. We found that alternation rates after both short and long delays were impaired at both ages in female 3xTgAD mice, indicative of robust spatial working memory deficits. For RAWM, again performance deficits were found in young 3xTgAD mice. As both tasks had similar efficacy at revealing early spatial memory deficits, we suggest that spontaneous behavioural protocols be prioritised over water maze testing in models such the 3xTgAD mouse as the former provide a far less stressful but equally effective alternative.

Probabilistic divergence time estimation without branch lengths: dating the origins of dinosaurs, avian flight and crown birds.

Branch lengths-measured in character changes-are an essential requirement of clock-based divergence estimation, regardless of whether the fossil calibrations used represent nodes or tips. However, a separate set of divergence time approaches are typically used to date palaeontological trees, which may lack such branch lengths. Among these methods, sophisticated probabilistic approaches have recently emerged, in contrast with simpler algorithms relying on minimum node ages. Here, using a novel phylogenetic hypothesis for Mesozoic dinosaurs, we apply two such approaches to estimate divergence times for: (i) Dinosauria, (ii) Avialae (the earliest birds) and (iii) Neornithes (crown birds). We find: (i) the plausibility of a Permian origin for dinosaurs to be dependent on whether Nyasasaurus is the oldest dinosaur, (ii) a Middle to Late Jurassic origin of avian flight regardless of whether Archaeopteryx or Aurornis is considered the first bird and (iii) a Late Cretaceous origin for Neornithes that is broadly congruent with other node- and tip-dating estimates. Demonstrating the feasibility of probabilistic time-scaling further opens up divergence estimation to the rich histories of extinct biodiversity in the fossil record, even in the absence of detailed character data.

Trabecular bone density of the proximal tibia as it relates to failure of a total knee replacement.

The relationship between post-operative bone density and subsequent failure of total knee replacement (TKR) is not known. This retrospective study aimed to determine the relationship between bone density and failure, both overall and according to failure mechanism. All 54 aseptic failures occurring in 50 patients from 7760 consecutive primary cemented TKRs between 1983 and 2004 were matched with non-failing TKRs, and 47 failures in 44 patients involved tibial failures with the matching characteristics of age (65.1 for failed and 69.8 for non-failed), gender (70.2% female), diagnosis (93.6% OA), date of operation, bilaterality, pre-operative alignment (0.4 and 0.3 respectively), and body mass index (30.2 and 30.0 respectively). In each case, the density of bone beneath the tibial component was assessed at each follow-up interval using standardised, calibrated radiographs. Failing knees were compared with controls both overall and, as a subgroup analysis, by failure mechanism. Knees were compared with controls using univariable linear regression. Significant and continuous elevation in tibial density was found in knees that eventually failed by medial collapse (p < 0.001) and progressive radiolucency (p < 0.001) compared with controls, particularly in the medial region of the tibia. Knees failing due to ligamentous instability demonstrated an initial decline in density (p = 0.0152) followed by a non-decreasing density over time (p = 0.034 for equivalence). Non-failing knees reported a decline in density similar to that reported previously using dual-energy x-ray absorptiometry (DEXA). Differences between failing and non-failing knees were observable as early as two months following surgery. This tool may be used to identify patients at risk of failure following TKR, but more validation work is needed.

Meeting increased demand for total knee replacement and follow-up: determining optimal follow-up.

The strain on clinic and surgeon resources resulting from a rise in demand for total knee replacement (TKR) requires reconsideration of when and how often patients need to be seen for follow-up. Surgeons will otherwise require increased paramedical staff or need to limit the number of TKRs they undertake. We reviewed the outcome data of 16 414 primary TKRs undertaken at our centre to determine the time to re-operation for any reason and for specific failure mechanisms. Peak risk years for failure were determined by comparing the conditional probability of failure, the number of failures divided by the total number of TKRs cases, for each year. The median times to failure for the most common failure mechanisms were 4.9 years (interquartile range (IQR) 1.7 to 10.7) for femoral and tibial loosening, 1.9 years (IQR 0.8 to 3.9) for infection, 3.1 years (IQR 1.6 to 5.5) for tibial collapse and 5.6 years (IQR 3.4 to 9.3) for instability. The median time to failure for all revisions was 3.3 years (IQR 1.2 to 8.5), with an overall revision rate of 1.7% (n = 282). Results from our patient population suggest that patients be seen for follow-up at six months, one year, three years, eight years, 12 years, and every five years thereafter. Patients with higher pain in the early post-operative period or high body mass index (≥ 41 kg/m(2)) should be monitored more closely.

Changes in tibial bone density measured from standard radiographs in cemented and uncemented total knee replacements after ten years' follow-up.

Stress shielding resulting in diminished bone density following total knee replacement (TKR) may increase the risk of migration and loosening of the prosthesis. This retrospective study was designed to quantify the effects of the method of fixation on peri-prosthetic tibial bone density beneath cemented and uncemented tibial components of similar design and with similar long-term survival rates. Standard radiographs taken between two months and 15 years post-operatively were digitised from a matched group of TKRs using cemented (n = 67) and uncemented (n = 67) AGC tibial prostheses. Digital radiograph densitometry was used to quantify changes in bone density over time. Age, length of follow-up, gender, body mass index and alignment each significantly influenced the long-term pattern of peri-prosthetic bone density. Similar long-term changes in density irrespective of the method of fixation correlated well with the high rate of survival of this TKR at 20 years, and suggest that cemented and uncemented fixation are both equally viable.

The role of the posterior cruciate ligament in total knee replacement.

OBJECTIVES: The purpose of this study was to examine the effect of posterior cruciate ligament (PCL) retention, PCL recession, and PCL excision during cruciate-retaining total knee replacement. METHODS: A total of 3018 anatomic graduated component total knee replacements were examined; 1846 of these retained the PCL, 455 PCLs were partially recessed, and in 717 the PCL was completely excised from the back of the tibia. RESULTS: Clinical scores between PCL groups favored excision for flexion (p < 0.0001), and recession and retention for stairs (p < 0.0001). There was a mild difference in long-term all-cause aseptic survivorship between PCL-retained (96.4% at 15 years) combined with PCL-recessed groups (96.6% at 15 years) when compared with the PCL-excised group (95.0% at 15 years) (p = 0.0411, Wilcoxon; p = 0.0042, log-rank), as well as tibial or femoral loosening, which reported prosthesis survival of 97.8% at 15 years for PCL-retained knees, 98.2% for recessed knees, and 96.4% for excised knees (p = 0.0934, Wilcoxon; p = 0.0202, log-rank). CONCLUSIONS: Despite some trade off in clinical performance, if the PCL is detached at the time of operation, conversion to a posterior-stabilised prosthesis may not be necessarily required as long as stability in the anteroposterior and coronal planes is achieved.

ERIDAS, a computer program for rapid calculation of internal doses from measurements of people in an emergency.

In an emergency involving the deliberate or accidental release of radioactive materials, there could potentially be a large number of people who require monitoring for internal contamination. Doses from these measurements will need to be calculated as quickly as possible. Emergency Response Internal Dose Assessment Software (ERIDAS) has been designed for this purpose.

Long-term deterioration of joint evaluation scores.

We investigated the long-term changes in the Harris Hip and Knee Society scores (HSS and KSS) to determine whether they result from overall functional decline rather than actual changes in the condition of the prosthesis. The HHS for 106 total hip arthroplasties with a minimum follow-up of ten years, no medical complications after operation and no evidence of radiological loosening, and the KSS for 264 total knee arthroplasties with a minimum follow-up of 12 years and no medical complications after operation or signs of radiographical loosening were evaluated. There were statistically significant drops in the functional scoring components of the joint evaluation systems despite no loosening of the prostheses or other significant medical complications. The HHS declined at an average of 0.67 points per year from between three and ten years after operation (p < 0.0001). Contributing to this were deterioration in gait and limp (p < 0.0004), the use of support aids (p < 0.0001), the distance walked (p < 0.0001) and the ability to climb stairs (p < 0.0455). The functional component of the KSS declined significantly at an average 0.88 points per year betwen the third and 12th years (p < 0.0001). There were significant declines in every component of the functional score including the distance walked (p < 0.0001), the ability to climb stairs (p < 0.0001) and the use of support aids (p < 0.0001). The knee score component of the KSS did not decline significantly (p < 0.9750). The combination of functional and pain scores within the HHS system leads to an inaccurate decline in the entire score. The decline of HHS and Knee Society functional scores in total joint arthroplasties, in the absence of implant-related problems, suggests that deterioration in the functional capacity of ageing patients is an important factor in longitudinal studies using these scoring systems.

Intra-operative findings in varus osteoarthritis of the knee. An analysis of pre-operative alignment in potential candidates for unicompartmental arthroplasty.

Interest in unicompartmental knee arthroplasty (UKA) for the treatment of medial compartment osteoarthritis has increased in recent years with apparent improvement in the long-term results. This is a result of improved surgical technique, patient selection, and implant design. In an effort further to improve patient selection we analysed the relationship between the pre-operative alignment of the knee and the anatomical findings at the time of surgery. We compared these findings with the indications for UKA. From 4021 total knee arthroplasties we compared intra-operative observations with the pre-operative clinical data in order to identify knees with isolated, medial, compartment changes, which would have been ideal candidates for UKA. We found that only 247 of the knees (6.1%) met anatomical qualifications for isolated, medial, unicompartmental osteoarthritis, and of these, only 168 (4.3%) met clinical standards ideal for UKA. Preoperative alignment showed a significant relationship with patterns of disease. Logistic regression revealed a relationship between pre-operative alignment and intraoperative findings resembling a Gaussian distribution. Patients with a pre-operative varus alignment of 7 degrees were slightly more likely to be selected for UKA. But the further the anatomical alignment in either direction varies from 7 degrees of varus, the more unlikely it is for the knee to exhibit a disease pattern of isolated, medial, unicompartmental osteoarthritis.

T-helper cell tolerance to ubiquitous nuclear antigens.

Systemic autoimmune diseases are characterized by the development of antinuclear autoantibodies. In order to understand the immunologic events leading to the development of such antibodies, knowledge of mechanisms of immune tolerance to nuclear antigens is required. By utilizing adoptive T-cell transfer strategies with transgenic mouse models expressing nuclear neo-self antigens, T-cell tolerance to the lupus-related nuclear antigens human La and nRNP A has been demonstrated. These findings also indicate the existence in normal animals of autoreactive B cells continuously presenting nuclear antigen, suggesting that nuclear antigens are not sequestered from the immune system. Investigations of CD4+ T-cell tolerance to non-nuclear antigens have revealed a number of mechanisms that protect the host from autoreactivity, including autoreactive T-cell deletion, regulatory T-cell development and anergy induction. Recent studies using T-cell receptor and neo-self nuclear antigen transgenic mice are revealing the importance of such mechanisms in maintaining tolerance to nuclear antigens. Mechanisms of tolerogenic antigen presentation, identification of tolerogenic antigen source(s) and the pathways leading to loss of tolerance to nuclear antigens in systemic autoimmune disease states are currently being sought.

Severe dating violence and quality of life among south carolina high school students.

BACKGROUND: Little research has addressed the impact of dating violence and forced-sex victimization and perpetration on adolescent well-being. In this cross-sectional study, we provide (1) estimates of severe dating violence (SDV) by victimization and perpetration status, (2) estimates of lifetime forced-sex victimization and perpetration, (3) demographic and health behaviors correlated with SDV, and (4) associations between SDV and forced sex and well-being as assessed by (1) health-related quality of life (H-R QOL) and (2) life satisfaction measures. METHODS: We used a stratified cluster sample of 5414 public high school students, grades 9 through 12, who responded to the 1997 self-administered South Carolina Youth Risk Behavior Survey. RESULTS: Nearly 12% of adolescents self-reported SDV as a victim (7.6%) or a perpetrator (7.7%), and SDV rates (victimization/perpetration combined) are higher in girls (14.4%) than boys (9.1%). Race, aggressive behaviors, substance use, and sexual risk-taking are correlates of SDV. Among young women, SDV victimization, not perpetration, was associated with recent poor H-R QOL and suicide ideation or attempts, but not lower life-satisfaction scores. Among young men, SDV perpetration, not victimization, was strongly associated with poor H-R QOL and suicide attempts, and lower scores for all domains of life satisfaction. CONCLUSIONS: This research provides evidence that SDV and forced sex are associated with poor H-R QOL, low life-satisfaction scores, and adverse health behaviors in adolescent female victims and male perpetrators. Screening for dating violence is needed to identify and intervene early to reduce the impact of dating violence.

Stalking perpetrators and psychological maltreatment of partners: anger-jealousy, attachment insecurity, need for control, and break-up context.

Two studies of the correlates of self-reported courtship persistence, stalking-like behaviors following a relationship break-up, and psychological maltreatment of partners were conducted in samples of male (N = 46 and 93) and female (N = 123 and 110) college students. Approximately 40% (38.5% and 44.6%) engaged in at least one stalking behavior following a break-up. A total of 10.7% (study 1) and 7.6% (study 2) engaged in 6 or more stalking behaviors. Stalking was significantly related to psychological maltreatment of the partner (PMP) prior to the break-up. Being the recipient of the breakup was associated with feelings of anger, jealousy and obsessiveness and with higher levels of courtship persistence, and stalking. A replicated path model showed that anxious attachment and need for control were related to PMP and that need for control had a direct contribution to stalking. For anxious attachment, its connection to stalking was indirect, mediated by the degree of anger-jealousy over the break-up.

Research on stalking: what do we know and where do we go?

Findings of the article in this two-volume series on stalking are reviewed. Building on the findings of the National Violence Against Women Survey (Tjaden & Thoennes, 1998), this series of studies adds to the literature in defining and measuring stalking behaviors. Repeated stalking victimization is reported by up to 62% of young adults, although frequencies depend on the sample and the precise definition used. Self-definitions of stalking victimization may be quite different from legal definitions. Although the majority of legally defined stalkers (where victim fear is a key component) are men stalking women, studies utilizing other definitions find many more women as stalkers, with no significant gender differences in many studies. In many cases, it does appear that stalking is one part of a larger pattern of relationship physical and psychological abuse. Data on emotional reactions and coping strategies of victims are also reviewed, along with findings on characteristics of stalkers.

The induction of SOS function in Escherichia coli K-12/PQ37 by 4-nitroquinoline oxide (4-NQO) and fecapentaenes-12 and -14 is bile salt sensitive: implications for colon carcinogenesis.

The response of Escherichia coli to genotoxic agents involves the triggering of a complex system of genes known as the SOS response. In E. coli PQ37, a test organism used for the assessment of genotoxicity, lacZ, the beta-galactosidase gene is placed under the control of sfiA, one of the SOS genes through an operon fusion. The induction of beta-galactosidase activity, when the organism is exposed to genotoxic agents, is an indirect measure of the genotoxic activity of the test compound. Incubation of E. coli PQ37 with either 4-nitroquinoline oxide (4-NQO) or one of the fecal mutagens, fecapentaene-12 or -14 (F-12 or F-14) in the presence of sodium taurocholate or sodium deoxycholate resulted in a significant enhancement of induction of beta-galactosidase activity. The molecular mechanisms of 4-NQO-induced mutagenesis in E. coli are similar to those of the effects of UV light in which both replication-dependent and repair-dependent pathways of mutagenesis exist. Since E. coli PQ37 is excision-repair-deficient, alternate pathways are involved in this system. Bile salts by themselves do not trigger the SOS response, and hence their role in enhancing the SOS-inducing potency of mutagens may involve the potentiation of the cleavage-inactivation of lexA (repressor of SOS) by the protein product of the SOS-controlled gene, recA. The potentiating effect of bile salts on the fecal mutagens, F-12 and F-14, has implications in their suspected role in colon carcinogenesis associated with high-fat, low-fiber diets.

Lectin binding to human colonocytes is predictive of colonic neoplasia.

OBJECTIVE: The aim of this study was to determine whether lectin binding to exfoliated human colonocytes could be used as a noninvasive test for colorectal polyps or cancer. METHODS: Colonocytes were harvested from 31 patients (10 controls, 10 with adenomatous polyps, and 11 with cancer), incubated with a panel of fluorescent-labeled lectins, and assayed by flow cytometry. RESULTS: The lectins jacalin (JAC) and wheat germ agglutinin (WGA) were useful in predicting the presence of a colorectal neoplasm (p = 0.0018 for JAC and p = 0.0099 for WGA). For JAC, sensitivity reached 81% with a specificity of 80%, and for WGA the sensitivity and specificity were both 75%. CONCLUSIONS: Lectin binding to human colonocytes can predict the presence of malignant and premalignant lesions of the colon, and has potential as a noninvasive screening tool for colorectal neoplasms.

An oral health promotion programme for nursing caries.

AIM: To evaluate an oral health promotion programme involving health visitors and mothers of 8-month-old babies in order to address some of the risk factors associated with nursing caries. DESIGN: Two cross-sectional studies using postal questionnaires. SAMPLE: A random sample of 250 mothers who had not received the oral health promotion programme and 250 mothers who had received the programme. SETTING: The City of Salford. RESULTS: The oral health promotion programme significantly improved mothers recall of advice given by health visitors encouraging the use of a feeder cup, brushing their babies' teeth with fluoride toothpaste and restricting sugary foods and drinks. Significant improvements were also found in recall of advice regarding the use of sugar-free medicine and registering babies with a dentist. The programme encouraged a higher proportion of the mothers to bring their children to clinics for a hearing check. CONCLUSION: A simple oral health promotion programme facilitated by health visitors improved recall of advice and clinic visiting behaviour.

Multiple signaling pathways regulate cell surface expression and activity of the excitatory amino acid carrier 1 subtype of Glu transporter in C6 glioma.

Neuronal and glial sodium-dependent transporters are crucial for the control of extracellular glutamate levels in the CNS. The regulation of these transporters is relatively unexplored, but the activity of other transporters is regulated by protein kinase C (PKC)- and phosphatidylinositol 3-kinase (PI3K)-mediated trafficking to and from the cell surface. In the present study the C6 glioma cell line was used as a model system that endogenously expresses the excitatory amino acid carrier 1 (EAAC1) subtype of neuronal glutamate transporter. As previously observed, phorbol 12-myristate 13-acetate (PMA) caused an 80% increase in transporter activity within minutes that cannot be attributed to the synthesis of new transporters. This increase in activity correlated with an increase in cell surface expression of EAAC1 as measured by using a membrane-impermeant biotinylation reagent. Both effects of PMA were blocked by the PKC inhibitor bisindolylmaleimide II (Bis II). The putative PI3K inhibitor, wortmannin, decreased L-[3H]-glutamate uptake activity by >50% within minutes. Wortmannin decreased the Vmax of L-[3H]-glutamate and D-[3H]-aspartate transport, but it did not affect Na+-dependent [3H]-glycine transport. Wortmannin also decreased cell surface expression of EAAC1. Although wortmannin did not block the effects of PMA on activity, it prevented the PMA-induced increase in cell surface expression. This trafficking of EAAC1 also was examined with immunofluorescent confocal microscopy, which supported the biotinylation studies and also revealed a clustering of EAAC1 at cell surface after treatment with PMA. These studies suggest that the trafficking of the neuronal glutamate transporter EAAC1 is regulated by two independent signaling pathways and also may suggest a novel endogenous protective mechanism to limit glutamate-induced excitotoxicity.

The effect of tibiotalar fixation on foot biomechanics.

Contact areas and peak pressures in the posterior facet of the subtalar and the talonavicular joints were measured in cadaver lower limbs for both the normal limb and after fixation of the tibiotalar joint. Six joints were fixed in neutral, in 5-7 degrees of varus and of valgus. Ten degrees of equinus angulation was also studied. Each position of fixation was tested independently. Neutral was defined as fixation without coronal or sagittal plane angulation compared with prefixation alignment of the specimen. When compared with normal unfused condition, peak pressures increased, and contact areas decreased in the subtalar joint for specimens fixed in neutral, varus, and valgus. However, the change in peak pressure for neutral fusion compared with normal control was not statistically significant (P > 0.07). Peak pressures for varus and valgus fixation were significantly different from normal (P < 0.001). Contact areas for all positions of fixation were significantly different from normal (P < 0.001). Coronal plane angulation, however, also resulted in significantly lower contact areas compared with neutral fixation (P < 0.001). Contact areas and peak pressures in the talonavicular joint did not appear to be substantially affected by tibiotalar fixation with coronal plane angulation. Equinus fixation qualitatively increased contact areas and peak pressures in the talonavicular and posterior facet of the subtalar joint. Neutral alignment of the tibiotalar joint in the coronal and sagittal planes altered subtalar and talonavicular joint contact characteristics the least compared with normal controls. Therefore, ankle fusion in the neutral position would be expected to most closely preserve normal joint biomechanics and may limit the progression of degenerative arthrosis of the subtalar joint.