Impregnation of antibiotic into porous high density polyethylene material (Medpor) using negative pressure.
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Anti-Bacterial Agents↗
Biomedical subjects
M J Perry
Publications and source records attributed to M J Perry.
Anti-de Sitter-space/conformal-field-theory Casimir energy for rotating black holes.
We show that, if one chooses the Einstein static universe as the metric on the conformal boundary of Kerr-anti-de Sitter spacetime, then the Casimir energy of the boundary conformal field theory can easily be determined. The result is independent of the rotation parameters, and the total boundary energy then straightforwardly obeys the first law of thermodynamics. Other choices for the metric on the conformal boundary will give different, more complicated, results. As an application, we calculate the Casimir energy for free self-dual tensor multiplets in six dimensions and compare it with that of the seven-dimensional supergravity dual. They differ by a factor of 5/4.
Journal Article↗
Migration up and down the urban hierarchy and across the life course.
In this article, we begin by reviewing the concept of step migration that originated in E. G. Ravenstein's seminal papers "The Laws of Migration" (1885, 1889). As a result of the forces of the Industrial Revolution underway in 19th century Great Britain, migrants moved from farms to villages, from villages to towns, from towns to county seats, and thence to large cities. Throughout much of the industrialization era in the United States, net population movements similarly were upward within the urban hierarchy, and step migration today remains widespread throughout much of the still developing world. Our investigations of recent data and trends, however, suggest that the latest U.S. migration-pattern regime is a strongly contrasting one. Many of the major movements in the system of internal (or domestic) migration are flows down the urban hierarchy, although we note highly differentiated patterns for persons and households at specific stages of the life course. We make use of the newly defined metropolitan and micropolitan Core-Based Statistical Areas (CBSAs) and a seven-level size typology to tabulate origin-destination-specific migration flow data from both Census 2000 and IRS tax-return administrative records for the period 1995-2000. We discuss the causes for net movements being either upward or downward in the national urban hierarchy, including the effects of spatially focused immigration, and movement preferences at various ages, including migration in young adulthood associated with entering and leaving college and the military, as well as moves characteristic of the stages of family formation, childrearing, and retirement.
Adolescent↗
Haplotypes of the low-density lipoprotein receptor-related protein 5 (LRP5) gene: are they a risk factor in osteoarthritis?
OBJECTIVE: Several genome-wide scans have revealed an osteoarthritis (OA)-susceptibility locus on chromosome 11q in close proximity to the low-density lipoprotein receptor-related protein 5 (LRP5) gene. The regulation of bone mass is under the control of LRP5 and since increased bone mass is thought to play a role in the pathology of OA we examined LRP5 polymorphisms and haplotypes to determine if variants of this locus may predispose to OA. METHODS: A UK control population of 187 individuals was examined for five commonly occurring polymorphisms against a cohort of 158 DNAs from patients with knee OA. An additional UK cohort was also examined to confirm the findings of the first study; this second group consisted of 110 knee OA patients. Haplotype analysis was also performed on patient and control DNAs. RESULTS: A study of individual polymorphisms revealed no association with disease. However, haplotype analysis of the initial two populations revealed a common haplotype (C-G-C-C-A) that provided a 1.6-fold increased risk of OA (P(c)=0.021). The data obtained from the second cohort confirmed the initial findings, with a 1.6-fold increased risk observed within this cohort for the risk haplotype (P=0.012). CONCLUSIONS: A closer investigation of LRP5 and associated Wnt signalling molecules in OA will help determine disease aetiology and the development of novel treatment strategies that specifically target the bone compartment.
Aged↗
Serum DDT, age at menarche, and abnormal menstrual cycle length.
BACKGROUND: Although dichlorodiphenyl trichloroethane (DDT) exposure is known to affect human endocrine function, few previous studies have investigated the effects of DDT exposure on age at menarche or menstrual cycle length. METHODS: A cross sectional study was conducted to study the effects of DDT exposure on age at menarche and menstrual cycle length among 466 newly married, nulliparous female Chinese textile workers aged 20-34 years enrolled between 1996 and 1998. Serum was analysed for DDT and its major metabolites. Multivariate linear regression was used to estimate DDT exposure effects on age at menarche and multivariate logistic regression was used to estimate DDT exposure effects on odds of experiencing short or long cycles. RESULTS: Relative to those in the lowest DDT quartile, the adjusted mean age at menarche was younger in those in the fourth quartile (-1.11 years). Modeled as a continuous variable, a 10 ng/g increase in serum DDT concentration was associated with an adjusted reduction in age at menarche of 0.20 years. Relative to those in the lowest DDT quartile, odds of any short cycle (<21 days) in the previous year were higher for those in the fourth quartile (odds ratio = 2.78; 95% CI 1.07 to 7.14). There were no associations between serum DDT concentrations and odds of experiencing a long cycle (>40 days). CONCLUSION: Results suggest that DDT exposure was associated with earlier age at menarche and increased risk of experiencing a shortened menstrual cycle.
Adult↗
Tamoxifen stimulates cancellous bone formation in long bones of female mice.
Selective estrogen receptor modulators (SERMs) have been developed as a means of targeting estrogen's protective effect on the skeleton in the treatment of postmenopausal osteoporosis. Although it is well established that SERMs such as tamoxifen inhibit bone resorption in a similar manner to estrogen, whether this agent shares estrogen's stimulatory action on bone formation is currently unclear. To address this question, we compared the effect of treatment for 28 d with 17beta-estradiol (E2; 0.1, 1.0 mg/kg x d) and tamoxifen (0.1, 1.0, or 10 mg/kg x d) on cancellous bone formation at the proximal tibial metaphysis of intact female mice. E2 stimulated the formation of new cancellous bone throughout the metaphysis. A similar response was observed after administration of tamoxifen, the magnitude of which was approximately 50% of that seen after E2. As expected, E2 was found to suppress longitudinal bone growth, but in contrast, this parameter was stimulated by tamoxifen. We conclude that tamoxifen acts as an agonist with respect to estrogen's stimulatory action on bone formation but as an antagonist in terms of estrogen's inhibition of longitudinal growth, suggesting that the protective effect of SERMs on the skeleton is partly mediated by stimulation of osteoblast activity.
Animals↗
Extended haplotypes and linkage disequilibrium in the IL1R1-IL1A-IL1B-IL1RN gene cluster: association with knee osteoarthritis.
The interleukin-1 gene cluster is a key regulator in a number of chronic disease processes. We explored the linkage between nine polymorphic loci in the IL1R1 promoter, eight in the IL1A-IL1B-IL1RN gene complex, and their association with osteoarthritis (OA), a common complex disease associated with low-level inflammation. Using 195 healthy controls, we identified eight novel polymorphisms in the IL1R1 exon 1A region. We found limited LD between IL1R1 and the IL1A-IL1B-IL1RN cluster, although LD within these two individual groups was high. To test association with knee OA, we genotyped 141 patients from Bristol (UK) at the 17 loci. IL1R1 promoter haplotypes showed no association with disease. However, within the IL1A-IL1B-IL1RN complex, we identified a common haplotype conferring a four-fold risk of OA (P=0.00043; Pc=0.0043) and one IL1B-IL1RN haplotype conferring a four-fold reduced risk (P=0.0036; Pc=0.029). To replicate these associations, we subsequently examined 163 knee OA patients from London. Here, the effects of the haplotypes were confirmed: the risk IL1A-IL1B-IL1RN haplotype conferred a two-fold risk of OA (P=0.02), and the protective IL1B-IL1RN haplotype conferred a five-fold reduced risk of OA (P=0.0000008). These results may help to explain the genome-wide scan linkage data and functional observations concerning association between IL-1 and OA.
Aged↗
Late presentation of alloplastic implant extrusion.
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Adult↗
4-thiophenoxy-N-(3,4,5-trialkoxyphenyl)pyrimidine-2-amines as potent and selective inhibitors of the T-cell tyrosine kinase p56lck.
We have developed a series of 4-thiophenoxy-N-(3,4,5-trialkoxyphenyl) pyrimidine-2-amines as potent and selective inhibitors of p56lck tyrosine kinase activity. In particular, the most potent inhibitor shows cellular activity in T-cell receptor (TCR) stimulated models of cytokine release, which suggests an immunomodulatory role for this class of inhibitor.
Adjuvants, Immunologic↗
Colonic dendritic cells, intestinal inflammation, and T cell-mediated bone destruction are modulated by recombinant osteoprotegerin.
Autoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of NFkappaB (RANKL). RANKL acting via its receptor, receptor activator of NFkappaB (RANK), increases bone turnover and promotes intestinal dendritic cell (DC) survival in vivo. Modulation of RANKL-RANK interactions with exogenous recombinant osteoprotegerin (Fc-OPG) reverses skeletal abnormalities and reduces colitis by decreasing colonic DC numbers. This study identifies a common causal link between bone disease and intestinal inflammation and establishes the importance of DC in mediating colonic inflammation in vivo.
Adjuvants, Immunologic↗
Luteinizing hormone receptor knockout (LuRKO) mice and transgenic human chorionic gonadotropin (hCG)-overexpressing mice (hCG alphabeta+) have bone phenotypes.
Considerable attention has been paid to the role of sex steroids during periods of major skeletal turnover, but the interaction of the gonadotropic hormones, which include LH, FSH, and human chorionic gonadotropin (hCG), within bone tissue have been overlooked. The question is pertinent due to the recent detection of extragonadal expression of gonadotropin receptors. Western blotting, immunolocalization, and RT-PCR supported the presence of osteoblast LH receptors. However, osteoblast cells failed to bind [(125)I]hCG and treatment with hCG failed to generate either cAMP or phosphorylated ERK 1/2. Bone mineral density (BMD) and bone histomorphometry were examined in the following models: 1) LH receptor null mutant (LuRKO) mice; 2) transgenic mice overexpressing hCG (hCG alphabeta+); and 3) ovariectomized (OVX) hCG alphabeta+ model. Male LuRKO mice showed a decrease in BMD after 5 months, apparently secondary to suppressed gonadal steroid production. Similarly, 9- to 10-wk-old female LuRKO mice exhibited decreases in histomorphometric parameters tested. The data indicate that loss of LH signaling results in a reduction in bone formation or an increase in bone resorption. By contrast, there were significant increases in BMD and histomorphometric indices for female, but not male, hCG alphabeta+ mice, indicating that chronic exposure to hCG results in bone formation or a decrease in bone resorption. However, OVX of the hCG alphabeta+ mice resulted in a significant reduction in BMD comparable to OVX WT controls. Although gonadotropin levels are tightly linked to sex steroid titers, it appears that their effects on the skeleton are indirect.
Adult↗
Multinucleated osteoclast formation in vivo and in vitro by P2X7 receptor-deficient mice.
The P2X7 receptor is a member of the family of P2X purinergic receptors, which upon sustained activation forms large pores in the plasma membrane. In cells of hematopoietic origin, P2X7 receptor activation has been shown to lead to multiple downstream events, including cytokine release, cell permeabilization, and apoptosis. This receptor has also been implicated in the generation of multinucleated giant cells, polykaryons, and osteoclasts. We have recently demonstrated that a blockade of this receptor inhibits osteoclast formation in vitro; therefore, we examined mice deficient in the P2X7 receptor in the context of bone. These mice were healthy and displayed no overt skeletal problems. Furthermore, we were able to demonstrate their ability to form multinucleated cells, in particular osteoclasts, both in vivo and in vitro. We also demonstrate the ability of P2X7R-/- multinucleated osteoclasts, upon stimulation with maitotoxin (MTX), to form pores in the plasma membrane in vitro. These findings are consistent with the existence of an endogenous pore structure present in osteoclast precursor cells that can be activated either by the P2X7 receptor, or in its absence, by alternative signals to mediate fusion and pore formation. These data provide further insight into the mode of action of the P2X7 receptor.
Animals↗
Estrogen-induced osteogenesis in intact female mice lacking ERbeta.
We recently found that estrogen receptor (ER) antagonists prevent high-dose estrogen from inducing the formation of new cancellous bone within the medullary cavity of mouse long bones. In the present investigation, we studied the role of specific ER subtypes in this response by examining whether this is impaired in female ERbeta(-/-) mice previously generated by targeted gene deletion. Vehicle or 17beta-estradiol (E(2)) (range 4-4,000 microg. kg(-1). day(-1)) was administered to intact female ERbeta(-/-) mice and wild-type littermates by subcutaneous injection for 28 days. The osteogenic response was subsequently assessed by histomorphometry performed on longitudinal and cross sections of the tibia. E(2) was found to cause an equivalent increase in cancellous bone formation in ERbeta(-/-) mice and littermate controls, as assessed at the proximal and distal regions of the proximal tibial metaphysis. E(2) also resulted in a similar increase in endosteal mineral apposition rate in these two genotypes, as assessed at the tibial diaphysis. In contrast, cortical area in ERbeta(-/-) mice was found to be greater than that in wild types irrespective of E(2) treatment, as was tibial bone mineral density as measured by dual-energy X-ray absorptiometry, consistent with previous reports of increased cortical bone mass in these animals. We conclude that, although ERbeta acts as a negative modulator of cortical modeling, this isoform does not appear to contribute to high-dose estrogen's ability to induce new cancellous bone formation in mouse long bones.
Animals↗
Effects of combination therapy with PTH and 17beta-estradiol on long bones of female mice.
Parathyroid hormone (PTH) is thought to increase trabecular bone mass in postmenopausal women by stimulating osteoblast function. A similar action may contribute to estrogen's protective effect on the skeleton, which we have explored in female mice, in which estrogen induces an exaggerated osteogenic response. In the present investigation, we used this model to determine whether an interaction exists between stimulatory effects of PTH and estrogen on osteoblast function in cancellous bone. An initial dose response study was performed where PTH (hPTH, 1-38) was administered to ten-week-old intact female mice by daily sc injection for 28 days, at doses of 1, 10, 100 microg/kg. In a subsequent study, intact female mice were given PTH and/or 17beta-estradiol (E2) 10 and 40 microg/kg/day respectively. Femoral BMD was assessed by peripheral DXA (PIXImus), and histomorphometry was performed to analyse changes in cancellous and cortical bone. PTH caused a small gain in femoral BMD, and increased the extent of periosteal bone formation surfaces, but had relatively little effect on other skeletal parameters when given alone. As previously found, E2 produced a large increase in femoral BMD, stimulated cancellous and endocortical bone formation, but inhibited periosteal bone formation. In mice treated with combination therapy, a greater increase in femoral BMD was observed compared to that following treatment with either agent alone. No differences in indices of cancellous bone were found between animals treated with E2 compared to the combination group. However, cortical area and periosteal bone formation rate were significantly greater in the latter group. We conclude that PTH and E2 exert an additive effect on bone mass in long bones of female mice, possibly reflecting an ability of PTH to oppose E2-induced suppression of periosteal bone formation.
Absorptiometry, Photon↗
Role of endothelial nitric oxide synthase in estrogen-induced osteogenesis.
It is well recognized that high-dose estrogen induces a marked osteogenic response in long bones of female mice. In light of evidence which suggests that nitric oxide synthase (NOS) plays a role in regulation of osteoblast activity, we analyzed whether NOS is involved in mediating this response. Intact female mice were administered 17beta-estradiol (E(2)) either alone or in combination with N(G)-nitro-L-arginine methylester (L-NAME) or aminoguanidine (AG), over 24 days. The former inhibits both constitutive and inducible isoforms of NOS, whereas the latter is a selective inhibitor of inducible NOS. Bone mineral density (BMD) of the femur was subsequently measured by dual-energy X-ray absorptiometry (DXA), and histomorphometry performed at the proximal metaphysis on longitudinal tibial sections. As expected, E(2) given alone led to a marked accumulation of cancellous bone at the proximal tibial metaphysis, associated with a significant gain in femoral BMD, and an increase in cancellous mineralizing surfaces as assessed by histomorphometry. Neither L-NAME nor AG affected cancellous histomorphometric indices when given alone. However, when administered in combination with L-NAME, the magnitude of the skeletal response to E(2) was significantly reduced. The tendency for L-NAME to reduce estrogen-induced bone formation within the proximal tibial metaphysis was more marked distally compared with proximally. In contrast, AG showed no tendency to suppress the osteogenic response to E(2). Subsequently, we examined the effect of E(2) administration on expression within mouse femoral bone marrow of endothelial NOS (eNOS), which is the predominant constitutive isoform of NOS within bone. No change in eNOS mRNA levels was observed following E(2) administration, as assessed by reverse transcription-polymerase chain reaction (RT-PCR). Taken together, our results suggest that eNOS plays a role in mediating estrogen-induced bone formation in intact female mice, possibly as a consequence of posttranscriptional regulation of eNOS activity by estrogen.
Animals↗
Genetic prodrug activation therapy (GPAT) in two rat prostate models generates an immune bystander effect and can be monitored by magnetic resonance techniques.
Treatment of hormone refractory prostate cancer requires new treatment strategies. Genetic prodrug activation therapy (GPAT) may provide a new therapeutic avenue. In this study the antitumour efficacy of the gene encoding herpes simplex virus thymidine kinase (HSVtk) activating the prodrug ganciclovir (GCV) was compared in two models of ectopic (subcutaneous) rat prostate cancer. Both models, which differ in their characteristics, were previously shown to be weakly immunogenic but susceptible to immunotherapy. Tumour cell lines were stably transfected with HSVtk and were rendered highly sensitive to GCV. Little or no bystander killing effect was observed by tk-transfected cells on wild-type cells in vitro. However, a significant in vivo bystander effect was observed suggesting an immune-mediated response. Indeed, such an immune response was capable of slowing the growth of distant wild-type tumours and increased overall animal survival. A T helper 1 immune response was generated as a result of GCV activation and cell kill, demonstrated by the secretion of IFNgamma by cultured splenocytes in response to tumour cells. BrDU staining of tk-transfected cells treated with GCV in vitro suggested apoptotic cell death, but Annexin V staining was less marked for one of the cell lines. Serial in vivo monitoring by non-invasive magnetic resonance spectroscopy (MRS) of the tk-transfected MATLyLu tumours demonstrated a decreased ATP/Pi ratio (a measure of cell energy status) during growth and an increase in the ATP/Pi ratio during regression initiated by treatment with GCV. Further, significant differences were found in the phosphomonester (PME) to total phosphate (SigmaP) ratios in treated compared with untreated tumours, a result rarely seen in animal models, but commonly observed in patients. This study showed that a Th1-biased immune response generated by killing prostate tumour cells with tk/GCV can kill distant as well as local wild-type tumour cells. These findings suggest that GPAT may have a potential application in patients with both confined and metastatic prostate cancer and MRS may provide a method of monitoring response to treatment.
Animals↗
Ranitidine bismuth citrate with clarithromycin alone or with metronidazole for the eradication of Helicobacter pylori.
BACKGROUND: Both triple therapy with ranitidine bismuth citrate (RBC) plus two antibiotics for 7 days and dual therapy of RBC with clarithromycin for 14 days have been extensively studied; both regimens effectively eradicate Helicobacter pylori. However, few studies have assessed the efficacy of dual therapy given for 7 days. AIM: To compare the efficacy and safety of RBC 400 mg with clarithromycin 500 mg, alone or with metronidazole 400 mg, given twice daily for 7 days for the eradication of H. pylori. METHODS: This single centre, randomized, double-blind study involved 118 patients with dyspepsia or a history of peptic ulcer disease. H. pylori infection was detected initially by CLO test, and confirmed in 109 patients by urea breath test and/or microbiology culture. H. pylori eradication was assessed 4 and 12 weeks after the end of treatment by urea breath test. H. pylori antibiotic susceptibility was assessed pre-study in all patients, and post-treatment in patients with a positive post-treatment urea breath test. Adverse events were recorded throughout the study. RESULTS: H. pylori was eradicated in 93% of patients who received RBC with clarithromycin and metronidazole and in 84% of patients who received RBC with clarithromycin (intention-to-treat rates). Per protocol eradication rates were 98% and 90% for triple therapy and dual therapy, respectively. The eradication of metronidazole-resistant H. pylori was achieved in 100% and 88% of patients following dual therapy and triple therapy, respectively, and acquired resistance to clarithromycin occurred in only one patient following treatment failure. Both treatments were well-tolerated; only one patient (2%) was withdrawn from each treatment group due to adverse events. CONCLUSIONS: RBC with clarithromycin and metronidazole is a highly effective and well-tolerated triple therapy regimen for the eradication of H. pylori. RBC with clarithromycin dual therapy has a similar efficacy, and offers an alternative to triple therapy when there are concerns about treatment with metronidazole or the use of multiple antibiotics. Both regimens are effective against antibiotic-resistant strains of H. pylori.
Adult↗
Pain after transrectal ultrasonography-guided prostate biopsy: the advantages of periprostatic local anaesthesia.
OBJECTIVE: To prospectively evaluate the efficacy and safety of periprostatic local anaesthesia (LA) during prostatic biopsy guided by transrectal ultrasonography (TRUS), as 20-65% of men report moderate to severe pain, and there is anecdotal and published evidence that periprostatic anaesthesia improves patients' tolerance. PATIENTS AND METHODS: In all, 157 patients were prospectively recruited and sequentially randomized to receive either LA or no anaesthesia. Sextant biopsies were taken in all men but some had more than six biopsies. All were asked to complete questionnaires immediately after TRUS-guided biopsy and for the subsequent week, giving pain scores and recording any morbidity, including symptoms of infection; analgesic use was also surveyed. RESULTS: Patients given LA had significantly lower pain scores at the time of biopsy than those given no anaesthesia, with median (sd) pain scores of 1.53 (0.7) and 1.95 (0.65) (P < 0.001), respectively. In addition, there was a trend towards less analgesic use by those given LA, although this was not statistically significant. There was no difference in the amount of haematuria, haematochezia or haematospermia, or infection rate, between the groups. The additional cost and time of the procedure was minimal ( pound3.00 and 3 min/per patient, respectively). CONCLUSION: Periprostatic LA infiltration is a quick and simple procedure which significantly improves immediate pain with no added morbidity; we strongly advocate its use to improve patient tolerance of TRUS-guided prostate biopsy.
Aged↗