Pelvic organ prolapse is associated with alteration of sphingosine-1-phosphate/Rho-kinase signalling pathway in human vaginal wall.

Pelvic organ prolapse (POP) is a debilitating condition of unknown aetiology affecting > 50% of women over 40 years of age. In POP patients, the vaginal walls are weakened allowing descent of pelvic organs through the vagina. We sought to determine if sphingosine-1-phosphate (S1P) signalling, which regulates smooth muscle contractility and apoptosis via the RhoA/Rho-kinase (ROK) pathway, is altered in the vagina of women with POP. Utilising anterior vaginal wall specimens, we provide novel demonstration of the S1P pathway in this organ. Additionally, comparing specimens from women having pelvic reconstructive surgery for POP and control subjects, we reveal increases in mRNA expression of the three major mammalian S1P receptors (S1P1-S1P3), and RhoA and the ROK isoforms: ROKα and ROKß in POP patients, which correlates with a decrease in elastic fibre assembly pathway constituents. Taken together, our data suggest the S1P/ROK pathway as a novel area for future POP research and potential therapeutic development.

Suppression of tumor cell growth both in nude mice and in culture by n-3 polyunsaturated fatty acids: mediation through cyclooxygenase-independent pathways.

Dietary n-3 polyunsaturated fatty acids (PUFAs), as compared with n-6 PUFAs, suppress cellular production of prostaglandins and tumor cell growth both in vitro and in vivo. However, the mechanism by which n-3 PUFAs suppress tumor growth is not understood. We investigated whether the suppression of tumor cell growth by dietary n-3 PUFAs is mediated through inhibition of cyclooxygenase (COX). A colon tumor cell line, HCT-116, that does not express COX was stably transfected with the constitutively expressed COX-1 or the inducible COX-2 cDNA using a retroviral transfection and infection system. Athymic nude mice transplanted with the cells expressing enzymatically active COX were fed isocaloric diets containing either safflower oil or fish oil for 2 weeks before the start of the experiment and for an additional 21 days after transplantation. Both tumor volume and tumor burden (tumor volume/body weight) were significantly reduced in mice fed the fish oil diet as compared with safflower oil-fed mice. This reduction occurred even in control mice that received injections with cells infected with the retroviral vector without COX-1 or COX-2 cDNA. The growth of tumor cells expressing COX was not different from the growth of those transfected with the vector alone in the nude mice and in soft agar. N-3 PUFAs, as compared with linoleic acid, also inhibited the growth of these cells in culture. This growth inhibition by n-3 PUFAs was not affected by COX-1 or COX-2 overexpression. Contrary to general belief, these results indicate that the suppression of tumor growth by dietary n-3 PUFAs is mediated through COX-independent pathways.

Receptor-mediated signaling pathways: potential targets of modulation by dietary fatty acids.

Extracellular signals are transmitted to intracellular targets through many signal-transduction pathways. Each signaling pathway is composed of a network of interacting signaling molecules that regulate diverse cellular responses. A modulation of the functional activities of these signaling molecules as a result of altered nutritional status could lead to qualitative and quantitative changes in cellular responses to extracellular signals. Growing evidence now suggests that fatty acids can directly and indirectly modulate signaling pathways at multiple levels. Elucidating the mechanism of this modulation could help us to understand how different types of dietary fat modify the risks of many chronic diseases.

Effect of citric acid on the nucleation of hydroxyapatite in a simulated body fluid.

The role of citric acid in a simulated body fluid (SBF) was examined with the main focus on its induction ability of hydroxyapatite (HAp) nucleation on a bioinert collagen membrane. Collagen membranes were soaked in the SBF with citric acid concentrations in the range of 0-4 mM; then, carbonate-containing HAp crystals grew within a limited range, i.e., 0.3-2 mM. The results were explained in terms of chemical interaction among calcium ion, citric acid and collagen membrane, especially strong chelation ability of citric acid with the calcium ion.

Biomimetic configurational arrays of hydroxyapatite nanocrystals on bio-organics.

Biomimetic configurational arrays of hydroxyapatite (HAp) nanocrystals on several bio-organics, collagen (Col), chondroitin sulfate (ChS), and their mixture, were comparatively studied. The nanocomposites of HAp/Col, HAp/ChS, and HAp/Col/ChS were synthesized through a precipitation method with calcium hydroxide suspension and phosphoric acid solution containing Col, ChS, and their mixture, respectively. The (0 0 2) diffraction of the synthesized HAp crystals on a Col fiber showed an around 60 arching angle, while that on a ChS fiber showed just around 10 degrees. The same configurational arrays of HAp crystals could also be obtained on the mixture of Col and ChS fibers. The different electron diffraction patterns of the HAp crystals on the Col and ChS fibers were explained by the different macromolecular configurations of the Col and ChS fibrils which compose their fibers. The results may be applicable to develop a bone substitute which mimics the peculiar configurational arrays of HAp crystals found in bone and their detailed organic composition.

A confirmatory factor analysis of the Center for Epidemiologic Studies Depression Scale in rheumatoid arthritis patients: additional evidence for a four-factor model.

OBJECTIVE: To examine the factor structure of the Center for Epidemiologic Studies Depression Scale (CES-D) in a sample of patients with rheumatoid arthritis (RA), testing all of the alternative models suggested by the previous evidence. METHODS: The CES-D was administered to a group of RA patients (n = 685) during a structured telephone interview. The telephone interview was repeated 6 months later (n = 537) and 12 months later (n = 453). Confirmatory factor analyses were conducted to test alternative models. RESULTS: The correlated 4-factor model and the second-order 4-factor model were the best fitting models. CONCLUSION: The factor structure of the CES-D previously found in the general population was replicated in an RA sample. The results are consistent with previous evidence of criterion contamination in the CES-D when used in an RA sample and provide support for the view that a single summary score may not be the most informative index of the CES-D.

Stress management in rheumatoid arthritis: what is the underlying mechanism?

OBJECTIVE: To test whether change in cognitive-behavioral variables (such as self-efficacy, coping strategies, and helplessness) is a mediator in the relation between cognitive behavior therapy and reduced pain and depression in persons with rheumatoid arthritis (RA). METHODS: A sample of patients with RA who completed a stress management training program (n = 47) was compared to a standard care control group (n = 45). A path analysis testing a model including direct effects of comprehensive stress management training on pain and depression and indirect effects via change in cognitive-behavioral variables was conducted. RESULTS: The path coefficients for the indirect effects of stress management training on pain and depression via change in cognitive-behavioral variables were statistically significant, whereas the path coefficients for the direct effects were found not to be statistically significant. CONCLUSION: Decreases in pain and depression following stress management training are due to beneficial changes in the arenas of self-efficacy (the belief that one can perform a specific behavior or task in the future), coping strategies (an individual's confidence in his or her ability to manage pain), and helplessness (perceptions of control regarding arthritis). There is little evidence of additional direct effects of stress management training on pain and depression.

Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates.

We present data on the lifetime prevalence of substance use, abuse and dependence in adolescents obtained through structured psychiatric interviews and self-report questionnaires. Most notably, we evaluate symptom profiles based on DSM-IV abuse and dependence criteria for tobacco, alcohol and marijuana, including a gender comparison. Participants are 3,072 adolescents (12-18 years) drawn from three community-based family samples in Colorado. Age trends suggest that substance use is a developmental phenomenon, which increases almost linearly from early to late adolescence. Substance use disorders are less common than experimentation in adolescence, but approximately 1 in 4 adolescents in the oldest cohorts meets criteria for abuse for at least one substance, and 1 in 5 meets criteria for substance dependence. By age 18 nearly 1 in 3 adolescents report daily smoking and 8.6% meet criteria for tobacco dependence. Although alcohol is the most commonly abused substance (10%), a slightly larger proportion of adolescents meet criteria for dependence on marijuana (4.3%) than alcohol (3.5%). Gender differences in prevalence of use more often show greater use in males than females. Males more frequently meet criteria for dependence on alcohol and marijuana in late adolescence, while females are more often nicotine dependent. A comparison of abuse and dependence symptom profiles shows some interesting variability across substances, and suggests that manifestations of a subset of symptoms are gender specific.

Doenjang hexane fraction-induced G1 arrest is associated with the inhibition of pRB phosphorylation and induction of Cdk inhibitor p21 in human breast carcinoma MCF-7 cells.

Doenjang (fermented soy paste) is a Korean traditional fermented food. In previous studies, we demonstrated that Doenjang extracts exhibited anti-mutagenic and anti-carcinogenic activities. Here we investigated the effects of Doenjang hexane fraction (DHF) on cell cycle progression in the human breast carcinoma MCF-7 cells. Treatment of DHF to MCF-7 cells induced a G1 phase arrest of the cell cycle, which correlated with the accumulation of the hypophosphorylated form of the retinoblastoma protein (pRB) and enhanced association of pRB with the transcription factor E2F-1. After DHF treatment, the expression of D-type cyclins was decreased in a time-dependent manner, but DHF did not affect the levels of cyclin-dependent kinases (Cdks), cyclin E and cyclin A protein. However, the activity of Cdk2 and cyclin E-associated kinase was decreased in a time-dependent manner. The tumor suppressor p53 and Cdk inhibitor p21, a known downstream effector of the p53, and association of p21 with Cdk2 were markedly induced in DHF-treated cells. Taken together, the present results indicate that treatment of MCF-7 cells with DHF induces a significant inhibition of pRB phosphorylation and increase of Cdk inhibitor p21 that appear to be responsible for the observed G1 arrest.

Inhibition of tyrosinase by green tea components.

The pigment melanin in human skin is a major defense mechanism against ultraviolet light of the sun, but darkened skin color, which is the result of increased and redistributed epidermal melanin, could be a serious aesthetic problem. Epidemiologically, it is well known that the consumption of green tea may help prevent cancers in humans and also reduce several free radicals including peroxynitrite. In the present study, to assess the efficacy of the inhibition of mushroom tyrosinase (monophenol monooxygenase EC 1.14.18.1), ten kinds of Korean traditional teas were screened for their tyrosinase inhibitory activity. Green tea was the strongest inhibitor, and the major active constituents in the tea are (-)-epicatechin 3-O-gallate (ECG), (-)-gallocatechin 3-O-gallate (GCG), and (-)-epigallocatechin 3-O-gallate (EGCG). All are catechins with gallic acid group as an active site. The kinetic analysis for inhibition of tyrosinase revealed a competitive nature of GCG with this enzyme for the L-tyrosine binding at the active site of tyrosinase.

Selective interference with verbal and spatial working memory in young and older adults.

Young and older adults were administered digit and location memory span tasks with and without verbal and spatial secondary tasks. Age differences were greater in location span than in digit span; however, there were no age differences in either the magnitude or pattern of effects of secondary tasks. There were also no age differences in the effects of secondary tasks on a combined (digit and location) task. On the digit and location span tasks, both young and older adults showed only domain-specific interference: naming colors selectively interfered with memory for digits, leaving memory for locations unaffected; pointing to matching colors selectively interfered with memory for locations, leaving memory for digits unimpaired. The results of the present study suggest a greater age deficit in spatial working memory than in verbal working memory, but provide no evidence of an age deficit in susceptibility to interference by secondary tasks in either domain.

Antimutagenic effect of plant flavonoids in the Salmonella assay system.

The antimutagenic effects of 27 kinds of plant flavonoids on the mutagenicity of aflatoxin B1(AFB1) and N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) in Salmonella typhimurium TA100 were investigated. In the mixed applications of AFB1 (1 microgram/plate) with the flavonoids (300 micrograms/plate) in the presence of a mammalian metabolic activation system (S9 mix), chrysin, apigenin, luteolin and its glucoside, kaempferol, fisetin, morin, naringenin, hesperetin, persicogenin, (+)-catechin and (-)-epicatechin showed the antimutagenic effect against AFB1 with more than 70% inhibition rate. A little or no antimutagenicities except flavone against MNNG (0.5 microgram/plate) were observed. For the antimutagenicity of the flavonoids on AFB1, the flavonoid structure that contains the free 5-, 7-hydroxyl group seemed to be essential. However, saturation of the 2,3-double bond or elimination of the 4-keto group did not affect the activity.

Distal radius fracture metaphyseal comminution: a new radiographic parameter for quantifying, the metaphyseal collapse ratio (MCR).

INTRODUCTION: Metaphyseal comminution is widely considered as a key radiographic parameter that predicts fracture instability for distal radius fractures. However, no quantitative parameter is available to measure this degree of comminution. To quantify metaphyseal comminution objectively, the authors devised and validated the metaphyseal collapse ratio, a new radiographic index. MATERIALS AND METHODS: Seventy-four cases of distal radius fracture in the elderly were included in this analysis. After closed reduction, a strictly lateral plain radiograph was obtained and digitally adjusted. The metaphyseal collapse ratio (MCR) was calculated expressing the maximal radiolucent extent as a percentage of the intercortical distance. Furthermore, correlations between MCR and age, gender, DXA scores, and other radiographic parameters, namely, radial shortening, volar tilt, radial inclination, and the presence of an associated ulnar fracture were investigated. RESULTS: Mean metaphyseal collapse ratio in the cohort was calculated to be 51.7% by one observer and 53.7% by a second, showing good interobserver and mean intraobserver reliability (0.812, P<0.001 and 0.826, P<0.001, respectively). MCR was found to be significantly correlated with conventionally accepted radiographic parameters of fracture instability, that is, radial shortening (P<0.001), volar tilt (P<0.001), and radial inclination (P=0.002), but not with age, gender, DXA scores, and the presence of a combined ulnar fracture. CONCLUSIONS: Metaphyseal collapse ratio, a novel radiographic parameter, was found to provide a reliable measure of metaphyseal comminution, and to be significantly correlated with other radiographic parameters that predict distal radius fracture instability. LEVEL OF EVIDENCE: Level III, diagnostic.

Factors affecting late displacement following volar locking plate fixation for distal radial fractures in elderly female patients.

The purpose of this study was to evaluate the risk of late displacement after the treatment of distal radial fractures with a locking volar plate, and to investigate the clinical and radiological factors that might correlate with re-displacement. From March 2007 to October 2009, 120 of an original cohort of 132 female patients with unstable fractures of the distal radius were treated with a volar locking plate, and were studied over a follow-up period of six months. In the immediate post-operative and final follow-up radiographs, late displacement was evaluated as judged by ulnar variance, radial inclination, and dorsal angulation. We also analysed the correlation of a variety of clinical and radiological factors with re-displacement. Ulnar variance was significantly overcorrected (p < 0.001) while radial inclination and dorsal angulation were undercorrected when compared statistically (p < 0.001) with the unaffected side in the immediate post-operative stage. During follow-up, radial shortening and dorsal angulation progressed statistically, but none had a value beyond the acceptable range. Bone mineral density measured at the proximal femur and the position of the screws in the subchondral region, correlated with slight progressive radial shortening, which was not clinically relevant. Volar locking plating of distal radial fractures is a reliable form of treatment without substantial late displacement.

Pre- and post-operative comorbidities in idiopathic carpal tunnel syndrome: cervical arthritis, basal joint arthritis of the thumb, and trigger digit.

We retrospectively reviewed 633 hands in 362 patients who had idiopathic carpal tunnel syndrome and underwent carpal tunnel release between 1999 and 2009. Electrophysiological studies and simple radiographs of the wrist, cervical spine, and basal joint of the thumb were routinely checked, and patients were also assessed for the presence of trigger digit or de Quervain's disease before and after surgery. Among 362 patients, cervical arthritis was found in 253 patients (70%), and C5-C6 arthritis was the most common site. Basal joint arthritis of the thumb was observed in 216 (34%) of the 633 hands. Trigger digit or de Quervain's disease was observed in 85 of the 633 hands (13%) before surgery, and developed in 67 hands (11%) after surgery. Cervical arthritis, basal joint arthritis, and trigger digit commonly coexist with idiopathic carpal tunnel syndrome. Patient education about these disorders is very important when they coexist with idiopathic carpal tunnel syndrome.

Characteristic radiographic features of the central ray in Apert syndrome.

We reviewed retrospectively seven patients with Apert acrosyndactyly and measured the size of the capitate ossification centre relative to that of the hamate and determined the relative position of the middle finger metacarpal relative to the ring finger metacarpal. We then compared those parameters in 197 normal children. In all patients, the middle finger metacarpal bone had migrated proximally relative to the ring finger metacarpal and the size of the capitate ossification centre was smaller than that of the hamate. After surgical release of the middle finger, relative proximal migration of the middle finger metacarpal was partially relieved and catch-up growth of the capitate was observed within several months. As fusion of the distal phalanges creates a diamond-shaped configuration, bone growth is markedly impaired in the middle finger ray. Therefore, early separation of the middle finger may be as important as early separation of the border digits.

Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase.

Genetic evidence indicating that TOLL-like receptor 4 (Tlr4) is the lipopolysaccharide (LPS) receptor in mice was reported. However, biochemical evidence that murine Tlr4 confers LPS responsiveness has not been convincingly demonstrated. Inducible cyclooxygenase (COX-2) is selectively expressed in LPS-stimulated macrophages in part mediated through the activation of NF kappa B. Thus, we determined whether murine Tlr4 confers LPS responsiveness as evaluated by the activation of NF kappa B and COX-2 expression. Transfection of a murine macrophage-like cell line (RAW264.7) with the constitutively active form (delta Tlr4) of Tlr4 is sufficient to activate NF kappa B and COX-2 expression. However, the truncated form (delta Tlr4(P712H)) of the missense mutant Tlr4(P712H) found in LPS-hyporesponsive mouse strain (C3H/HeJ) inhibits LPS-induced NF kappa B activation and COX-2 expression. The inability of delta Tlr4(P712H) to activate NF kappa B and induce COX-2 expression is rescued by a constitutively active adapter protein myeloid differentiation factor 88 (MyD88), which interacts directly with the cytoplasmic domain of Tlr proteins. Furthermore, MyD88 is co-immunoprecipitated with the wild-type delta Tlr4 but not with the delta Tlr4(P712H) mutant. Together, these results indicate that Tlr4 confers LPS responsiveness in RAW264.7 cells and suggest that hyporesponsiveness of C3H/HeJ mice to LPS is attributed to the disruption of Tlr4-mediated signaling pathways that results from the inability of the mutant Tlr4(P712H) to interact with MyD88.

Triangular-shaped incisor crowns and crowding.

The purpose of this study was to establish if there is a correlation between the shape of the labial crowns of the incisors and crowding. Plaster cast models of 69 untreated individuals (30 males and 39 females) were evaluated. The casts were selected randomly from the collection at Seoul National University and Ajou University. With the use of Little's irregularity index, the sample was divided into 2 groups, a crowded group and a normal group. Repeated measurements of the maximum mesiodistal width of the incisal and cervical areas of the incisors were taken by means of a digital vernier caliper and a ratio of these measurements was calculated. The mean value for the crowded group was significantly larger in the incisal area (P <.01) and smaller in the cervical areas (P <.01) than corresponding values in the normal group. These ratios were correlated with the irregularity index (Pearson r(2) from 55% to 65%). The value obtained from the incisor width ratio in the normal group can be useful for the diagnosis and treatment of crowded malocclusion.

Hydroxyapatite formation on cellulose cloth induced by citric acid.

Hydroxyapatite (HAp) formation on cellulose cloth with the aid of citric acid was investigated. The cellulose cloths were soaked in simulated body fluid (SBF) solutions (1.5 SBF) with ion concentrations 1.5 times that of SBF (1.0 SBF) with and without citric acid and carbonate containing HAp crystals were found to form only in the 1.5 SBF solution that contained citric acid. The results were explained in terms of hydrogen bonding of citric acid to the cellulose cloth and its chelating ability of calcium ions. Practical application may involve the inclusion of citric acid in the 1.5 SBF solution to promote formation of HAp on previously bioinert cellulose cloth.