Effects of prenatal dexamethasone exposure on adult C57BL/6J mouse metabolism and oxidative stress.

Prenatal glucocorticoid exposure has been shown to alter hypothalamic-pituitary-adrenal axis function resulting in altered fetal development that can persist through adulthood. Fetal exposure to excess dexamethasone, a synthetic glucocorticoid, has been shown to alter adult behaviour and metabolism. This study investigated the effects prenatal dexamethasone exposure had on adult offspring cardiac and liver metabolism and oxidative stress. Pregnant C57BL/6 mice received a dose of 0.4 mg/kg dexamethasone on gestational days 15-17. Once pups were approximately 7 months old, glucose uptake was determined using positron emission tomography and insulin resistance (IR) was determined by homeostatic model assessment (HOMA) IR calculation. Oxidative stress was assessed by measuring 4-hydroxynonenal protein adduct formation and total reactive oxygen species. Female dexamethasone group had significantly increased glucose uptake when insulin stimulated compared to vehicle-treated mice. HOMA IR revealed no evidence of IR in either male or female offspring. There was also no change in oxidative stress markers in either cardiac or liver tissues of male or female offspring. These data suggest that prenatal dexamethasone exposure in male mice does not alter oxidative stress or metabolism. However, prenatal dexamethasone exposure increased glucocorticoids, cardiac glucose uptake, and pAkt signaling in female heart tissues in adult mice, suggesting there are sex differences in prenatal dexamethasone exposure.

Intervention with Microfinance for AIDS and Gender Equity (IMAGE): Women's Engagement with the Scaled-up IMAGE Programme and Experience of Intimate Partner Violence in Rural South Africa.

The Intervention with Microfinance for AIDS and Gender Equity (IMAGE) programme has been scaled up to three provinces in South Africa. This paper explores associations between women's engagement in the intervention, intimate partner violence (IPV) and factors associated with IPV and partner abuse. We enrolled women receiving group-based microfinance loans plus gender training into the scaled-up IMAGE cohort study (n = 860). We present cross-sectional analysis on participants' characteristics and intervention engagement and use multivariate logistic regression to explore associations. 17% of women reported lifetime (95% CI 15 to 20%) and 7% past year (95% CI 5 to 9%) IPV, 9% past-year economic (95% CI 7 to 11%) and 11% past-year emotional (95% CI 9 to 14%) abuse. Women under 35 years had higher levels of IPV and emotional abuse. 53% of women attended all the trainings, 83% continuously borrowed and 98% agreed the training had a major impact on their life. Attendance was associated with improved partner relationships (χ2p < 0.001), but not lower IPV risk. Odds of past-year IPV decreased the more types of support (e.g. advice) women received from group members (aOR 0.27, p < 0.001 among those reporting all support versus none or some). A similar pattern was seen for economic, but not emotional, abuse. The scaled-up IMAGE intervention is widely acceptable and may support improvements in partner relationships, but younger women need to be targeted. Group support appears to be a potentially important component of the intervention.

The effects of exercise and active assisted cycle ergometry in post-operative total knee arthroplasty patients - a randomized controlled trial.

PURPOSE: The purpose of this study was to examine the effect of the use of an active assisted cycle ergometer as an adjunct to post-operative treatment following total knee arthroplasty. METHOD: A total of 55 participants aged 50-80 years who had undergone unilateral total knee arthroplasty were randomly assigned to either the control group (standard of care) or the active assisted cycle ergometer (AACE) group. The effect on patient motivation, blood biomarkers, and knee pain, function, range of motion (ROM), strength, and swelling was examined. Qualitative feedback was also obtained post-operatively. RESULTS: Although there was no statistically significant difference in the standard of care compared to the AACE group, there was a trend for a greater reduction in knee pain on the visual analog scale, improved Lower Extremity Functional Scale scores, and knee extension ROM and strength. A greater percentage of the experimental group demonstrated higher motivation. There was no significant difference in swelling or blood biomarker measures. Qualitative feedback from the AACE group post-operatively was also positive. CONCLUSIONS: The use of an AACE protocol as an adjunct to total knee arthroplasty rehabilitation may improve post-operative clinical outcomes. This study has been registered at clinicaltrials.gov (identifier NCT02265523 , Oct 16 2014). LEVEL OF EVIDENCE: Level 1 - randomized controlled trial. Further research with a larger sample size is needed to confirm the benefits of the ergometer use.

Major histocompatibility complex restriction fragment length polymorphisms define three diabetogenic haplotypes in BB and BBN rats.

Class I and II major histocompatibility complex (MHC) probes can be used to subdivide diabetes-prone BB rats and their BBN control strain, coderived from the same outbred colony by selection against diabetes. Class II probes (A-alpha in particular) distinguish four restriction fragment length polymorphisms (RFLP), termed 1a, 1b, 2a, and 2b, in the BBN population, only one of which (2a) is found in BB rats. The degree of class II RFLP in the population studied is RT1.B-alpha greater than or equal to RT1.B-beta greater than RT1.D-alpha greater than or equal to RT1.D-beta, suggesting that intra-class II region dynamics may be different in rats compared with mice. A class I probe (S16) absolutely distinguished BB from BBN rats, since all BB rats exhibit an RFLP pattern termed 2a0, while 2a BBN rats can be subdivided into 2a1 and 2a2 forms. Serologic evaluation has shown that 2a0, 2a1, and 2a2 rats express RT1.AuBu, 1a rats express RT1.AaDa, and 1b rats express neither RT1a nor RT1u at the loci tested. A breeding study was carried out to determine the diabetogenicity of the MHC-defined RFLP's. As expected, the BB-derived 2a0 is diabetogenic. The BBN-derived 2a1 and 2a2 RFLPs are also diabetogenic, while 1a and 1b rats do not carry MHC-linked diabetogenic genes. The MHC-linked diabetes gene acts in a functionally recessive manner, since there is a 10-fold higher incidence in homozygotes than in heterozygotes. Analysis of the RFLP patterns leads us to hypothesize that the 2a1 RFLP results from a crossover between 1a and 2a0 MHCs and that the diabetogenic MHC-linked gene is on the class II side of Qa and T1. The availability of three diabetogenic MHC haplotypes should help localize the MHC-linked diabetogenic gene of rats.

Looking into teeth with ultrasound.

Ultrasound is readily conducted across a boundary when the specific acoustic impedances of the two media are about equal. The specific acoustic impedance of dental enamel is about that of aluminum. A longitudinal sonic pulse, less than 250 nanoseconds in duration, conducted to the tooth through an aluminum rod, has positively detected the enamel-dentin junction as well as the dentin-pulp interface.

Dental enamel: detection of surface changes by ultrasound.

Evidence indicates that the tooth surface differs in structure from the enamel immediately beneath it, and particularly that the enamel rod type structure is minimal in the true natural surface. Furthermore, the rod ends appear to disappear with age after the eruption of the tooth. The thickness of the surface layer may be as much as 25 micrometers. Studies of caries incidence show a peak in the attack curve 2 to 4 years after eruption and a decline thereafter for all teeth. This information indicates that the mechanical structure of the tooth surface should be carefully studied. A highly useful means appears to be ultrasound since the specific acoustic impedance of highly mineralized tissue like enamel is strongly dependent on fraction volume mineralization and since non-destructive test techniques can be based on ultrasonics. An experimental demonstration of ultrasonic detection in vitro of tooth surface demineralization is given.

The role of partnership dynamics in determining the acceptability of condoms and microbicides.

Microbicides are a class of substances under development that could reduce the sexual transmission of HIV and other sexually transmitted diseases when applied locally to genital mucosal surfaces. Microbicide acceptability research has largely focused on product characteristics, rather than processes of negotiation within relationships about use. Gender relations, decision-making power and communication within sexual relationships are recognised as important determinants of condom and contraceptive use, and are likely to determine microbicide use also. As part of social science research linked to the Microbicides Development Programme (MDP) we combine relationship-based theories with anthropological work conducted with women and men using a placebo gel. We explore communication and decision-making in gel and condom use, including constructions of risk and trust. During the MDP301 Phase III pilot study, in-depth interviews were conducted at sites in South Africa, Tanzania, Uganda and Zambia. Following four weeks of placebo gel use, women and their partners were asked about gel use and acceptability, partner involvement, sexual practices and condom use. Data from 45 couples at five sites were analysed using a grounded theory approach in NVivo. Participation in the study did not require women to inform their partners, yet our data shows women seeking permission from their partners, negotiating disclosure, exchanging information and persuading or motivating for gel use. Although gel was supposedly 'woman-controlled', men exercised considerable influence in determining whether and how it was used. Despite this, negotiations around use were largely successful, since the gel increased sexual pleasure and provided opportunities for intimate communication and the building of trust. Decisions about condom and microbicide use are made in a dyadic context and involve a complex negotiation of risk and trust. Whilst preferences relating to product characteristics are largely individual, use itself is dependent on partnership dynamics and the broader social context in which sexual risk management occurs.

Neutron diffraction studies of collagen in fully mineralized bone.

Neutron diffraction measurements have been made of the equatorial and meridional spacings of collagen in fully mineralized mature bovine bone and demineralized bone collagen, in both wet and dry conditions. The collagen equatorial spacing in wet mineralized bovine bone is 1.24 nm, substantially lower than the 1.53 nm value observed in wet demineralized bovine bone collagen. Corresponding spacings for dry bone and demineralized bone collagen are 1.16 nm and 1.12 nm, respectively. The collagen meridional long spacing in mineralized bovine bone is 63.6 nm wet and 63.4 nm dry. These data indicate that collagen in fully mineralized bovine bone is considerably more closely packed than had been assumed previously, with a packing density similar to that of the relatively crystalline collagens such as wet rat tail tendon. The data also suggest that less space is available for mineral within the collagen fibrils in bovine bone than had previously been assumed, and that the major portion of the mineral in this bone must be located outside the fibrils.

N-Alkylated aziridines are easily-prepared, potent, specific and cell-permeable covalent inhibitors of human ß-glucocerebrosidase.

ß-Glucocerebrosidase deficiency leads to Gaucher disease and is a potential marker of Parkinson's disease. We have identified N-octyl conduritol aziridine as a potent and specific covalent inactivator of GBA1 in living cells. This compound is a promising lead towards a positron emission tomography probe intended to image GBA1 activity.

Comparison of dosage-dependent effects of beta-aminopropionitrile, sodium fluoride, and hydrocortisone on selected physical properties of cortical bone.

BAPN, sodium fluoride, and hydrocortisone are reported to induce altered mineralization states. Three separate sets of experiments, one set for each agent, were performed using male New Zealand white rabbits. In each experiment the rabbits were segregated into groups, each fed a specified weight-determined dose for 13 weeks and then sacrificed. Compact bone from the left femur and tibia were tested for density, composition, sonic velocity, longitudinal elastic modulus, equatorial diffraction spacing of mineralized collagen, diaphyseal cross-sectional area, and relative load stress. beta-Aminopropionitrile (BAPN) induced monotonic degradation of all properties at all dose levels, corresponding to the decreasing density with dosage level. The elastic moduli show a decrease; the equatorial diffraction spacing of the collagen increases. The cross-sectioned diaphysis resembled woven bone. The variability in properties increased with dosage. The total cross-sectional area for a given weight increased, implying that the decreased elastic properties were compensated for by a larger area to support the weight. There was a slight increase in average density and other properties for fluoride-treated rabbits, peaking at 20 mg/kg BW/day. For higher dosages the properties are degraded and the values were much lower at high fluoride dosages than for BAPN. There was no peak for the equatorial diffraction spacing, which increased with dosage. It is inferred that the fluorosed apatite is denser than normal apatitic mineral and therefore has a smaller specific volume. A greater weight fraction of fluorosed mineral has a smaller volume fraction than the equivalent normal apatitic mineral. The bone sections look more normal, except for the porosis. The total cross-sectional area decreases when the bone density increases and then increases as the density falls, again implying that the area required to support body weight depends on the magnitude of the elastic moduli. There was a small change in some of the properties of the bones of the hydrocortisone-treated rabbits, but the effects on others were undetectable within the uncertainty of the procedures. There was no change in the cross-sectional areas of the diaphyses.

Serum triiodothyronine determination in clinical use.

Two radioimmunassays for the determination of serum triiodothyronine (T3) were developed. The assay of T3 in unextracted serum had several advantages over the assay on extracted serum and was chosen for the routine determination of T3 in serum from 117 patients requiring assessment of their thyroid status. In 53 subjects considered retrospectively not to have thyroid dysfunction nor to have been on steroid contraceptives or therapy, the pooled mean serum T3 concentration was 1-92 (actual range 0-88-2-62) nmol/l. A significant inverse relationship was observed between the serum T3 level and the age of the subject. Serum total T3 levels discriminate clearly between hypo-,eu- and hyperthyroid patients and provide a rather more sensitive index of hyperthyroid function than total serum T4. In the face of normal serum T4 the T3 level was depressed in five patients with marked hypoproteinaemia and elevated in two patients taking heroin.

Radioimmunoassay kits for thyroid hormones.

Characteristics of the T4 and T3 radioimmunoassay kits that are commercially available in the UK are described. Useful comparative data and criticism are given about many of these kits. Some unacceptable variation in accuracy is demonstrated.

Glycogen and glycogen phosphorylase associated with sarcoplasmic reticulum: effects of fatiguing activity.

The purpose of the present study was to investigate the effects of fatiguing muscular activity on glycogen, glycogen phosphorylase (GP), and Ca(2+) uptake associated with the sarcoplasmic reticulum (SR). Tetanic contractions (100 ms, 75 Hz) of the gastrocnemius and plantaris muscles, elicited once per second for 15 min, significantly reduced force to 26.5 +/- 4.0% and whole muscle glycogen to 23% of rested levels. SR glycogen levels were 415.4 +/- 76.6 and 20.4 +/- 2.1 microg/mg SR protein in rested and fatigued samples, respectively. The optical density of GP from SDS-PAGE was reduced to 21% of control, whereas pyridoxal 5'-phosphate concentration, a quantitative indicator of GP content, was significantly reduced to 3% of control. GP activity after exercise, in the direction of glycogen breakdown, was reduced to 4% of control. Maximum SR Ca(2+) uptake rate was also significantly reduced to 81% of control. These data demonstrate that glycogen and GP associated with skeletal muscle SR are reduced after fatiguing activity.

Modification of etching patterns in bovine dental enamel.

It is presumed that the etching pattern is controlled by the residual organic content of dental enamel. Pretreatment with 1.ON NaOH sould remove the organic material and modify the etching pattern. SEM studies and other tests for physical and chemical properties show that the predicted modification of the etching pattern, when the tooth surface is pretreated with NaOH solution, occurs apparently without other changes or properties.

Ultrasonic measurements of deer antler, bovine tibia and tympanic bulla.

Longitudinal sonic plesio-velocity, density and mineral volume fraction of the three bone types plus bovine bone matrix are reported. The axial sonic velocity in km/s and the mineral volume fraction for each is as follows: deer antler 3.08, 0.33; bovine tibia 3.89, 0.44; tympanic bulla 4.53, 0.85; bovine matrix 1.82. A brief discussion of the deer antler and tympanic bulla histology is included.

Sonic velocity and attenuation in wet compact cow femur for the frequency range 5 to 100 MHz.

Ultrasonic studies on bone have not been done as intensively as other tissues, probably because there is less opportunity to examine bone in vivo by this modality. There is considerable interest in using ultrasonics to learn about the material properties of bone for which purpose the sonic spectrum may be useful. The longitudinal sonic velocity and attenuation have been found for several sections from one sample of wet cow femur for both the axial and radial directions over the frequency range of 5 to 100 MHz. The basic technique was solid-to-solid contact using a fused quartz buffer rod coupled to the bone specimen. There is clear evidence of velocity dispersion which Lakes et al. (1986) did not find over a frequency range up to 16 MHz. While there seems to be a peak in both velocity and attenuation at 70 MHz, it is necessary to obtain measurements at higher frequencies to make sure this is not an artifact. The axial sonic velocity varied from 4.29 km/s at 5 MHz to 4.447 km/s at 50 MHz, while the radial velocity was 3.45 km/s at 5 MHz and increased to 3.62 km/s at 50 MHz. The attenuation coefficient axially started at a mean value of 3.5 db/mm at 5 MHz and increased to a mean of 19 db/mm at 100 MHz. The corresponding radial attenuation coefficients are 5.2 and 26, respectively.

The variation of sonic plesio-velocity in dose dependent lathyritic rabbit femurs.

It has been hypothesized that the origin of the increased elastic modulus of mineralized bone compared with the demineralized bone matrix is in the higher crosslinking density of the collagen in bone. Osteolathyrism is ascribed to an inhibition of crosslinking of the collagen by the lathyrogen and should be accompanied by a decrease in the elastic modulus of the bone. Dose dependent osteolathyrism was induced by varying the amount of BAPN ingested per day by young New Zealand white rabbits until they were mature. The femurs exhibited dose dependent properties, including wet bone density and sonic plesio-velocity in the radial direction. It was found that there is no minimum critical dose. Even though no overt osteolathyritic stigmata could be observed, both the sonic properties and the wet bone density could be affected at any dose level. The sonic plesio-velocity and the longitudinal elastic modulus decreased with BAPN dose level, most rapidly at the lower dose levels and then less so at higher dosages. Since BAPN acts to inhibit the crosslinking density, it appears that the elastic moduli of bone are dependent on the crosslinking density.

A phase II study of carboplatin and vinorelbine in patients with poor prognosis small cell lung cancer.

AIM: The aim of this study was to evaluate the activity of the combination of carboplatin and vinorelbine in patients with poor prognosis small cell lung cancer (SCLC). Patients with good prognosis disease were included who were not medically fit to tolerate conventional chemotherapy. Activity was assessed primarily as response rate and secondarily in terms of toxicity, time to progression and survival. PATIENTS AND METHODS: Fifty-eight patients, 37 men and 21 women, with histologically or cytologically confirmed SCLC, who had bi-dimensionally measurable disease, with ECOG performance status > or = 2, with adequate haematological, hepatic and renal function received first-line chemotherapy with carboplatin (AUC x 5) day 1 and vinorelbine (30 mg/m2) days 1 and 8 of a 28-day cycle. Response was assessed after every two cycles of chemotherapy, with patients receiving a maximum of six cycles of treatment. RESULTS: The combination of carboplatin and vinorelbine is an active regimen in the treatment of SCLC, with an overall intention-to-treat response rate of 55% [95% confidence interval (CI): 42-68%] with six (10%) of patients having a complete response. Median time to progression was 18 weeks (95% CI: 15-21 weeks). Median overall survival was 26 weeks (95% CI: 21-31 weeks). Ten patients failed to complete two cycles of treatment, and were not evaluable for response for the following reasons: septic death (1 neutropaenic, 1 no myelotoxicity), non-toxic death (1 tumour eroded through the pulmonary artery, 1 ischaemic heart disease) ischaemic heart disease (1) and patient decision (5). There were a total of three toxic deaths all sepsis-complicating neutropaenia. Forty-four (76%) patients experienced grade 3 or 4 neutropaenia, six (11%) grade 3 or 4 thrombocytopaenia, 10 (13%) grade 3 lethargy, three (5%) grade 3 nausea and two (3%) grade 3 diarrhoea. CONCLUSIONS: The combination of carboplatin and vinorelbine is active against SCLC but the toxicity profile in this group of patients suggests that further evaluation is not appropriate.

X-ray diffraction analysis of tendon collagen at ambient and cryogenic temperatures: role of hydration.

Equatorial (d) and meridional (D) spacings of native rat tail tendon (RTT) and unmineralized native turkey leg tendon (UTLT) were measured at ambient and liquid-nitrogen temperatures, using X-ray diffraction. Cooling of air-dried RTT or UTLT caused little change in d, which was approximately equal (1.1 nm) in the two tissues before and after cooling. For fully hydrated RTT or UTLT, cooling caused the familiar broad equatorial diffraction pattern to increase in sharpness to more resemble the pattern seen in dehydrated tissue. The d-spacings of hydrated RTT and UTLT fell by 0.12 nm (8.5%) and 0.19 nm (13%), respectively to values seen (at ambient temperature) when the tissue water content is the maximum possible in the absence of unbound water (0.5 g water/g dry collagen). These results can be explained by the movement of water within the fibril. In tissue with a water content of greater than 0.5 g/g dry collagen the spacings reflecting the lateral packing of the axially-linked tropocollagen molecules comprising a collagen fibril are determined partly by the unbound component of intermolecular hydration. As the bulk water between the fibrils freezes, this mobile component remains initially unfrozen as the tissue is cooled below zero degree C. It diffuses from the intermolecular spaces into the interfibrillar spaces where it also rapidly freezes. This allows the d-spacing to decrease to the value appropriate for the presence of bound intermolecular water only. The mechanism is likely to be an energetically favourable relaxation of the lateral positions of the tropocollagen molecules from a quasi-hexagonal arrangement to hard-disk liquid-like packing. The results and methods of this study may be applicable in the elaboration of more complex collagenous systems.